5H-indeno 1,2-b!pyrazine-2,3-dione derivatives, their preparation and medicinal products containing them

ABSTRACT

Compounds of formula (I): ##STR1## wherein R represents a CR 4  R 5 , CHR 6 , or C═R 7  radical and R 3  represents an oxygen atom, salts thereof, the preparation thereof and drugs containing same. The compounds of formula (I) have valuable pharmacological properties and are alpha-amino-3-hydroxy-5-methyl-4-osoxaziepropionic acid (AMPA) receptor antagonists, said receptor also being known as the quisqualate receptor. Furthermore, the compounds of formula (I) are non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, and particularly NMDA receptor glycine modulation site ligands.

The present invention relates to compounds of formula: ##STR2## andtheir salts, to their preparation and to medicinal products containingthem.

In the formula (I),

--R represents an N-alk, C(R₄)R₅, CH--R₆ or C═R₇ radical,

--R₁ and R₂, which may be identical or different, represent hydrogen orhalogen atoms or alkyl, alkoxy, amino, --N═CH--N(alk)alk', nitro, cyano,phenyl, imidazolyl, SO₃ H, hydroxyl, polyfluoroalkoxy, carboxyl,alkoxycarbonyl, --NH--CO--NR₁₁ R₁₂, --N(alk)--CO--NR₁₁ R₁₂,--N(alk-Ar)--CO--NR₁₁ R₁₂, --NH--CS--NR₁₁ R₁₂, --N(alk)-CS--NR₁₁ R₁₂,--NH--CO--R₁₁, --NH--CS--R₂₄, --NH--C(═NR₂₇)--NR₁₀ R₁₂,--N(alk)--C(═NR₂₇)--NR₁₀ R₁₂, --CO--NR₁₀ R₁₂, --NH--SO₂ --NR₁₀ R₁₂,--N(alk)--SO₂ --NR₁₀ R₁₂, --NH--SO₂ --CF₃, --NH--SO₂ -alk, --NR₁₀ R₁₃,--S(O)_(m) -alk-Ar or --SO₂ --NR₁₀ R₁₂ radicals or2-oxo-1-imidazolidinyl radicals in which position 3 is optionallysubstituted with an alkyl radical or 2-oxo-1-perhydropyrimidinylradicals in which position 3 is optionally substituted with an alkylradical,

--R₃ represents an oxygen atom or an NOH, NOalk or NOalkAr radical,

--R₄ represents an alkyl, -alk-Het or phenylalkyl radical in which thephenyl ring is optionally substituted with one or more substituentschosen from halogen atoms and alkyl, alkoxy, nitro, amino, hydroxyl,cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals,

--R₅ represents an alkyl (1-11C in an unbranched or branched chain),-alk-Het, --NR₈ R₉, --NH--CHO, --NH--COOR₁₇, --NH--SO₂ R₂₄, --COOR₁₀,-alk-COOR₁₀, -alk-CONR₁₀ R₁₈, -alk-NR₁₀ R₁₈, -alk-OH or -alk-CN radical,a phenylalkyl radical in which the phenyl ring is optionally substitutedwith one or more substituents chosen from halogen atoms and alkyl,alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and-alk-COOR₁₀ radicals, an --NH--CO--Ar radical in which Ar is optionallysubstituted with one or more substituents chosen from halogen atoms andalkyl, alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and-alk-COOR₁₀ radicals, an --NH--CO-Het, --NH--CO-alk-Het,--NH--CO-alk-COOR₁₀ or --NH--CO-alk-NR₁₀ R₁₈ radical, an --NH--CO-alk-Arradical in which Ar is optionally substituted with one or moresubstituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino,hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals, a1-pyrrolyl radical optionally substituted with a --COOR₁₀ radical, an--NH--CO--NH-alk-Ar radical in which Ar is optionally substituted withone or more substituents chosen from halogen atoms and alkyl, alkoxy,nitro, amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀radicals, an --NH--CO--NH-Het or --NH--CO--NH-alk-Het radical, an--NH--CO--NH--Ar radical in which Ar is optionally substituted with oneor more substituents chosen from halogen atoms and alkyl, alkoxy, nitro,amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals, oran --NH--COalk, --NH--Cocycloalkyl, --NH--CO--NH-alk or --NH--CO--NH₂radical, or alternatively R₄ and R₅, together with the carbon atom towhich they are attached, form a cycloalkyl radical,

--R₆ represents a hydrogen atom or a hydroxyl, alkyl (1-11C in anunbranched or branched chain), -alk-OH, --NR₁₄ R₁₅, -alk-NR₁₄ R₁₅,-alk-Het, --NH--CHO, --COOalk, -alk-COOR₁₀ or -alk-CO--NR₁₀ R₁₈ radical,a phenylalkyl radical in which the phenyl ring is optionally substitutedwith one or more substituents chosen from halogen atoms and alkyl,alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and-alk-COOR₁₀ radicals, an --R₁₆ --COOR₁₀ or --CO--COOR₁₀ radical or a1-pyrrolyl radical optionally substituted with a --COOR₁₀ radical,

--R₇ represents an oxygen atom or an NOH, NO-alk-COOR₁₀, NO-alk, CHR₁₉,NR₁₀, C(COOR₁₀)R₂₀ or C(CONR₁₀ R₂₁)R₂₀ radical,

--R₈ represents a hydrogen atom or an alkyl, -alk-COOR₁₀, -alk-NR₁₀ R₂₁or -alk-Het radical or a phenylalkyl radical in which the phenyl ring isoptionally substituted with one or more substituents chosen from halogenatoms and alkyl, alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂,--COOR₁₀ and -alk-COOR₁₀ radicals,

--R₉ represents a hydrogen atom or an alkyl radical,

--R₁₀ represents a hydrogen atom or an alkyl radical,

--R₁₁ represents a hydrogen atom or an alkyl (1-9C in an unbranched orbranched chain), alkoxy, -alk-COOR₁₀, -alk-Het or -alk-NR₁₂ R₁₀ radical,a phenylalkyl radical in which the phenyl ring is optionally substitutedwith one or more substituents chosen from halogen atoms and alkyl,alkoxy, nitro, amino, hydroxyl, -alk-NH₂, carboxyl, alkoxycarbonyl,cyano and -alk-COOR₁₀ radicals, a phenyl radical optionally substitutedwith one or more substituents chosen from halogen atoms and alkyl,alkoxy, nitro, amino, hydroxyl, -alk-NH₂, carboxyl, alkoxycarbonyl,cyano and -alk-COOR₁₀ radicals, or a -Het radical,

--R₁₂ represents a hydrogen atom or an alkyl radical,

--R₁₃ represents an alkyl, Het or alkoxycarbonyl radical,

--R₁₄ and R₁₅, which may be identical or different, each represent analkyl radical, or alternatively R₁₄ represents a hydrogen atom and R₁₅represents a hydrogen atom or an alkyl, --COR₂₂, --CSR₂₃ or --SO₂ R₂₄radical,

--R₁₆ represents a --CHOH or --CH(OH)alk(1-5C)-chain,

--R₁₇ represents an alkyl or phenylalkyl radical,

--R₁₈ represents a hydrogen atom or an alkyl radical,

--R₁₉ represents a hydroxyl, alkyl, -alk-Het, --NR₂₅ R₂₆, -alk-COOR₁₀ or-Het radical, a phenyl radical optionally substituted with one or moresubstituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino,hydroxyl, -alk-NH₂, --COOR₁₀, cyano and -alk-COOR₁₀ radicals, or aphenylalkyl radical in which the phenyl ring is optionally substitutedwith one or more substituents chosen from halogen atoms and alkyl,alkoxy, nitro, amino, hydroxyl, -alk-NH₂, --COOR₁₀, cyano and-alk-COOR₁₀ radicals,

--R₂₀ represents a hydrogen atom or an alkyl radical,

--R₂₁ represents a hydrogen atom or an alkyl radical,

--R₂₂ represents an alkyl, cycloalkyl, --COOalk or -alk-COOR₁₀ radical,a phenyl radical optionally substituted with one or more substituentschosen from halogen atoms and alkyl, alkoxy, nitro, amino, hydroxyl,-alk-NH₂, --COOR₁₀, cyano and -alk-COOR₁₀ radicals, a phenylalkylradical in which the phenyl ring is optionally substituted with one ormore substituents chosen from halogen atoms and alkyl, alkoxy, nitro,amino, hydroxyl, -alk-NH₂, --COOR₁₀, cyano and -alk-COOR₁₀ radicals, an-alk-NR₁₀ R₁₂ radical, an --NH--Ar radical in which Ar is optionallysubstituted with one or more substituents chosen from halogen atoms andalkyl, alkoxy, nitro, amino, hydroxyl, -alk-NH₂, --COOR₁₀, cyano and-alk-COOR₁₀ radicals, a -Het, -alk-Het or --OR₁₇ radical, an --NH-alk-Arradical in which Ar is optionally substituted with one or moresubstituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino,hydroxyl, -alk-NH₂, --COOR₁₀, cyano and -alk-COOR₁₀ radicals, or an--NH-alk-Het, --NH-alk, --NH₂ or --NH-Het radical,

--R₂₃ represents an --NH-alk, --NH--Ar, --NH-Het or --NH₂ radical,

--R₂₄ represents an alkyl or phenyl radical,

--R₂₅ and R₂₆, which may be identical or different, each represent analkyl or cycloalkyl radical,

--R₂₇ represents a hydrogen atom or an alkyl radical,

-alk represents an alkyl or alkylene radical,

-alk' represents an alkyl radical,

--m is equal to 0, 1 or 2,

--Ar represents a phenyl radical,

-Het represents a saturated or unsaturated, mono- or polycyclicheterocycle containing 1 to 9 carbon atoms and one or more hetero atoms(O, S, N), optionally substituted with one or more alkyl, phenyl orphenylalkyl radicals,

on the understanding that, when R₁ and R₂ represent hydrogen atoms andR₃ represents an oxygen atom, R is not a radical (a) C═R₇ in which R₇represents an oxygen atom or an NOH radical, or (b) CH--R₆ for which R₆represents a hydroxyl radical.

Except where otherwise stated, in the foregoing definitions and thosewhich follow, the alkyl, alkylene and alkoxy radicals and portionscontain 1 to 6 carbon atoms and are unbranched- or branched-chainradicals, the acyl radicals and portions contain 2 to 4 carbon atoms,the cycloalkyl radicals contain 3 to 6 carbon atoms and halogen atomsare chosen from fluorine, chlorine, bromine and iodine.

Preferably, Het is chosen from pyrrolyl, pyridyl, pyrimidinyl,imidazolyl, thiazolyl, oxazolinyl, thiazolinyl, pyrazinyl, tetrazolyl,triazolyl, pyrrolidinyl, piperazinyl, piperidyl, thienyl, furyl,azetidinyl and imidazolinyl rings, all these heterocycle beingoptionally substituted with one or more alkyl, phenyl or phenylalkylradicals. Preferred substituents are methyl, phenyl and benzyl radicals.

Preferred polyfluoroalkoxy radicals are trifluoromethoxy radicals.

The compounds of formula (I) for which R represents a C═R₇ radical forwhich R₇ represents an NO-alk, C(COOR₁₀)R₂₀ or C(CONR₁₀ R₂₁)R₂₀ or CHR₁₉radical and/or R₃ represents an NOH, NOalk or NOalkAr radical possessisomeric forms (E and Z). These isomers and the mixtures thereof formpart of the invention.

The compounds of formula (I) for which R represents a CH--R₆ radical andR₆ represents a --CO--COOR₁₀ radical possess tautomeric forms (E and Z).These tautomeric forms also form part of the invention.

The enantiomers and diastereoisomers of the compounds of formula (I) forwhich R represents a C(R₄)R₅ or CH--R₆ radical also form part of theinvention.

The compounds of formula (I) for which R represents an N-alk, C(R₄)R₅ orCH--R₆ radical, R₆ represents a hydrogen atom and R₃ represents anoxygen atom may be prepared by cyclization, in the presence of ammoniumacetate, of a derivative of formula: ##STR3## in which R represents anN-alk or C(R4)R₅ radical or a CH--R₆ radical in which R₆ represents ahydrogen atom, R₁ and R₂ have the same meanings as in the formula (I)and Ra represents an alkoxy radical.

This reaction is preferably performed in acetic acid, at the boilingpoint of the reaction medium.

The derivatives of formula (II) may be obtained by the action of achloride ClCOCORa in which Ra is an alkoxy radical on a derivative offormula: ##STR4## in which R represents an N-alk or C(R₄)R₅ radical or aCH--R₆ radical in which R₆ represents a hydrogen atom and R₁ and R₂ havethe same meanings as in the formula (I).

This reaction is generally performed in an inert solvent such astetrahydrofuran, in the present of a tertiary amine such astriethylamine, at a temperature of between 0 and 25° C.

The derivatives of formula (III) may be obtained by application oradaptation of the methods described in the examples and by P. W. NEBERet al., Justus Liebigs Ann. Chem., 526, 277 (1936), V. S. VELEZHEVA etal., Khim. Farm. Zh., 24, 46 (1990) (Chem. Abstracts, 114, 228786) andYUHPYNG L. CHEN et al., J. Med. Chem., 35(8), 1429 (1992).

The compounds of formula (I) for which R represents an N-alk radical ora CH--R₆ radical in which R₆ represents a hydrogen atom and R₃represents an NOH, NOalk or NOalkAr radical may be prepared by theaction of a corresponding compound of formula (I) for which R₃represents an oxygen atom on a derivative H₂ NORb in which Rb representsa hydrogen atom or an alkyl radical or an -alkAr radical in whichradicals alk and Ar have the same meanings as in the formula (I).

This reaction is generally performed in an inert solvent such as analcohol (for example ethanol), dioxane or water, at the boiling point ofthe reaction medium.

The compounds of formula (I) for which R represents a C═R₇ radical inwhich R₇ represents an oxygen atom may be prepared by hydrolysis of thecorresponding compounds of formula (I) for which R represents a C═R₇radical and R₇ represents an NOH radical.

This reaction is generally performed by means of an acid, in an aqueousmedium, at the boiling point of the reaction medium. As an acid,hydrochloric acid is preferably used.

The compounds of formula (I) for which R represents a C═R₇ radical andR₇ represents an NOH radical may be prepared by the action of an alkylnitrite on a corresponding compound of formula (I) for which Rrepresents a CH--R₆ radical and R₆ represents a hydrogen atom.

This reaction is preferably performed in an inert solvent such asdimethyl sulphoxide, in the presence of an alkali metal hydride such assodium hydride, at a temperature in the region of 20° C. Preferably,isoamyl nitrite is used.

The compounds of formula (I) for which R represents a C═R₇ radical andR₇ represents an NO-alk-COOR₁₀ or NO-alk radical may be prepared by theaction of a corresponding compound of formula (I) for which R representsa C═R₇ radical and R₇ represents an NOH radical on a halide Hal-Rc forwhich Hal represents a halogen atom and Rc represents an alkyl or-alk-COOR₁₀ radical, alk and R₁₀ having the same meanings as in theformula (I).

This reaction is preferably performed in the presence of a base such asan alkali metal hydride, for instance sodium hydride, in an inertsolvent such as dimethyl sulphoxide, at a temperature in the region of20° C.

The derivatives Hal-Rc for which Rc represents an -alk-COOR₁₀ radicalare commercially available or may be obtained by the action ofHal-alk-Hal in which Hal represents a halogen atom and alk represents analkyl radical on an alkali metal cyanide (sodium or potassium cyanide),in a water/alcohol mixture, at a temperature between 0° C. and theboiling point of the reaction medium, followed by the action of a strongacid such as hydrochloric acid, in the presence of an alcohol (forexample methanol, ethanol), at a temperature between 0° C. and theboiling point of the reaction medium.

The compounds of formula (I) for which R represents a C═R₇ radical andR₇ represents a CHR₁₉ radical in which R₁₉ represents a hydroxyl radicalmay be prepared by hydrolysis of the corresponding compounds of formula(I) for which R₁₉ represents an --NR₂₅ R₂₆ radical.

This reaction is preferably performed by means of an acid such ashydrochloric acid, in an aqueous medium, at a temperature of between 20and 40° C.

The compounds of formula (I) for which R represents a C═R₇ radical andR₇ represents a CHR₁₉ radical in which R₁₉ represents an --NR₂₅ R₂₆radical may be prepared by the action of a corresponding compound offormula (I) for which R represents a --CH--R₆ radical and R₆ representsa hydrogen atom on a derivative HC (Rd) (Re) Rf in which either Rd andRf, which may be identical or different, each represent an --NR₂₅ R₂₆radical in which R₂₅ and R₂₆ have the same meanings as in the formula(I) and Re represents an alkoxy radical such as a tert-butoxy radical,or Rd, Re and Rf, which are identical, each represent an --NR₂₅ R₂₆radical in which R₂₅ and R₂₆ have the same meanings as in the formula(I).

This reaction is generally performed in an inert solvent such asdimethylformamide, at a temperature of between 20 and 40° C.

The derivatives HC (Rd) (Re) Rf may be obtained by application ofadaptation or the method described by H. BREDERECK, Liebigs Ann. Chem.,762, 62 (1972).

The compounds of formula (I) for which R represents a C═R₇ radical, R₇represents a CHR₁₉ radical and R₁₉ represents an alkyl, optionallysubstituted phenyl or -alk-Het radical, a phenylalkyl radical in whichthe phenyl ring is optionally substituted or a -Het or -alk-COOR₁₀radical may be prepared by the action of a corresponding compound offormula (I) for which R represents a CH--R₆ radical and R₆ represents ahydrogen atom on an aldehyde of formula OHC--Rg in which Rg representsan alkyl radical, a phenyl radical optionally substituted with one ormore substituents chosen from halogen atoms and alkyl, alkoxy, nitro,amino, hydroxyl, -alk-NH₂, --COOR₁₀, cyano and -alk-COOR₁₀ radicals, an-alk-Het radical, a phenylalkyl radical in which the phenyl ring isoptionally substituted with one or more substituents chosen from halogenatoms and alkyl, alkoxy, nitro, amino, hydroxyl, -alk-NH₂, --COOR₁₀,cyano and -alk-COOR₁₀ radicals, or a -Het or -alk-COOR₁₀ radical inwhich radicals alk, Het and R₁₀ have the same meanings as in the formula(I).

This reaction is generally performed either in an inert solvent such asdimethylformamide, 1,2-dimethoxyethane, a lower aliphatic alcohol (forexample methanol, ethanol) or a mixture of these solvents, in thepresence of a base such as sodium hydroxide, potassium hydroxide or astrong organic base such as 1,8-diazabicyclo 5.4.0!undec-7-ene, at atemperature of between 20 and 100° C., or in dimethyl sulphoxide, in thepresence of an alkali metal hydride such as sodium hydride, at atemperature in the region of 20° C., or in the presence oftetrabutylammonium bromide and a base such as an alkali metal hydroxide(for example sodium hydroxide, potassium hydroxide), in dimethylsulphoxide, at a temperature between 20° C. and the boiling point of thereaction medium, or in acetic acid or acetic anhydride, in the presenceof ammonium acetate, at a temperature between 20° C. and the boilingpoint of the reaction medium.

The derivatives OHC--Rg are commercially available or may be obtained(a) by oxidation of the corresponding alcohols HOH₂ C--Rg (using K₂ Cr₂O₇ in a sulphuric acid medium; CrO₃ in pyridine or MnO₂ in a chlorinatedsolvent (for example dichloromethane) at a temperature in the region of20° C., or using dimethyl sulphoxide and ClCO--COCl by adaptation orapplication of the method described by D. SWERN et al., J. Org. Chem.,44, 4148 (1979)); (b) by reduction of the corresponding carboxylic acidsHOOC--Rg (using lithium aluminum hydride or AlH₃, in an inert solventsuch as tetrahydrofuran, at a temperature of between 0 and 25° C.); (c)by reduction of the corresponding esters alkOOC--Rg (usingdiisobutylaluminium hydride, in an inert solvent such as toluene, at atemperature of between -70° C. and 25° C., or lithium aluminum hydride,in an inert solvent such as tetrahydrofuran, at a temperature of between0 and 25° C.).

The corresponding alcohols HOH₂ C--Rg for which Rg represents an-alk-Het radical or an alk--Ar radical in which Ar is optionallysubstituted are commercially available or may be obtained from thecorresponding organometallic compounds by application or adaptation ofthe methods described by N. S. NARASIMHAN et al., Tetrahedron Lett., 22(29), 2797 (1981); L. ESTEL et al., J. Het. Chem., 26, 105 (1989); N. S.NARASIMHAN et al., Synthesis, 957 (1983); H. W. GSCHWEND et al., Organicreactions, 26, I (1979); V. SNIEKUS, Chem. Rev., 90, 879 (1990) and F.MARSAIS et al., J. Heterocyclic Chem., 25, 81 (1988). Preferably, theorganolithium or organomagnesium derivative of the heterocycle or of theoptionally substituted benzene is reacted with formaldehyde, ethyleneoxide or a derivative Hal-alk-CH₂ OP where P is a protective group (forexample methyl ether, tetrahydropyranyl ether, benzyl ether ortriethylsilyl ether), Hal is a halogen atom and alk an alkyl radical,followed by liberation of the alcohol function, by application oradaptation of the methods described by W. GREENE et al., ProtectingGroups in Organic Synthesis, second edition, 1991, John Wiley ans sons.

The corresponding alcohols HOH₂ C--Rg for which Rg represents an-alk-Het radical or an -alk-Ar radical in which Ar is optionallysubstituted may also be obtained by reduction of the correspondingcarboxylic acids or esters by means of lithium aluminum hydride, in aninert solvent such as tetrahydrofuran or diethyl ether, at the boilingpoint of the reaction medium.

The alcohols HOH₂ C--Rg for which Rg represents an -alk-Het radical mayalso be obtained by application or adaptation of the method described byJ. Th. MEYER et al., Helv. Chem. Acta, 65, 1868 (1982), from thederivatives Hal-H₂ C-alk(0-5C)-Het, which are themselves obtained by theaction of a halogenating agent, (halogenated derivative of phosphorus orthionyl chloride) from a corresponding derivative HOH₂ C-alk(0-5C)-Het,optionally in an inert solvent such as dichloromethane, at a temperatureof between 20 and 40° C.

The corresponding carboxylic acids HOOC--Rg for which Rg represents a-Het or -alk-Het radical or an -alk-Ar radical in which Ar is optionallysubstituted are commercially available or may be obtained from thecorresponding optionally substituted benzenes and heterocycles byapplication or adaptation of the methods described by L. ESTEL et al.,J. Heterocyclic Chem., 26, 105 (1989); N. S. NARASIM HAN et al.,Synthesis, 957 (1983); A. TURCK et al., Synthesis, 881 (1988); A. J.CLARKE et al., Tetrahedron Lett, 27, 2373 (1974); A. R. KATRITZKY etal., Org. Perp. Procedure Int., 20 (6), 585 (1988); N. FURUKAWA et al.,Tetrahedron Lett., 28 (47), 5845 (1987); H. W. GSCHWEND et al., OrganicReactions, 26, 1 (1979) and V. SNIECKUS, Chem. Rev., 90, 879 (1990).Preferably, the corresponding organometallic derivative of theheterocycle or of the corresponding optionally substituted benzene (forexample organolithium, organomagnesium derivative) is prepared andreacted either with CO₂ or with a derivative Hal-alk-COOalk in which Halrepresents a halogen atom and alk an alkyl radical, followed by ahydrolysis of the ester.

The derivatives Hal-alk-COOalk are commercially available or prepared bythe action of Hal-alk-Hal in which Hal represents a halogen atom on analkali metal cyanide such as sodium or potassium cyanide, in awater/alcohol mixture, at a temperature between 0° C. and the boilingpoint of the reaction medium, followed by the action of an acid such ashydrochloric acid, in the presence of an alcohol, at a temperaturebetween 0° C. and the boiling point of the reaction medium.

The corresponding esters alkOOC--Rg are commercially available or may beobtained from the acids by the action of an organic acid such ashydrochloric acid or sulphuric acid, in the alcohol also serving asesterifying agent, at the boiling point of the reaction medium.

The derivatives Hal-alk-Hal are commercially available or may beobtained from the corresponding dihydric alcohols by application oradaptation of the methods described by C. LAROCK, "Comprehensive OrganicTransformations", Ed. VHC, page 353 (1989).

The derivatives HOC--Rg for which Rg represents an -alk-COOR₁₀ radicalare commercially available or may be obtained by reduction of thecorresponding carboxylic acids, by application or adaptation of themethods described by H. C. BROWN et al., J. Am. Chem. Soc., 106, 8001(1984) and J. Org. Chem., 52, 5400 (1987). The corresponding acids arecommercially available or may be obtained by application or adaptationof the methods described by H. HUNSDIECKER et al., Chem. Ber., 75, 256(1942) and R. F. NAYLOR, J. Chem. Soc., 1108 (1947).

The compounds of formula (I) in which R represents a C═R₇ radical and R₇represents an NRIo radical may be prepared by the action of ethyltrifluoroacetate on a corresponding compound of formula (I) for which Rrepresents a CH--R₆ radical, R₆ represents an --NR₁₄ R₁₅ radical, R₁₄represents a hydrogen atom and R₁₅ represents a hydrogen atom or analkyl radical.

This reaction is generally performed in an inert solvent such asdimethylformamide, at a temperature in the region of 60° C.

The compounds of formula (I) for which R represents a C═R₇ radical andR₇ represents a C(COOR₁₀)R₂₀ radical may be prepared by dehydration of aderivative of formula: ##STR5## in which R₁, R₂ and R₃ have the samemeanings as in the formula (I) and Rh represents a --C(R₂₀) (OH)--COOR₁₀radical in which R₂₀ and R₁₀ have the same meanings as in the formula(I).

This reaction is generally performed in acetic anhydride, at the boilingpoint of the reaction medium.

The derivatives of formula (IV) for which R₁, R₂ and R₃ have the samemeanings as in the formula (I) and Rh represents a --C(R₂₀) (OH)--COOR₁₀radical in which R₂₀ and R₁₀ have the same meanings as in the formula(I) may be obtained by the action of a corresponding compound of formula(I) for which R represents a CH--R₆ radical and R₆ represents a hydrogenatom on a derivative R₂₀ --CO--COOR₁₀ for which R₁₀ and R₂₀ have thesame meanings as in the formula (I), followed by treatment with aceticacid.

This reaction is performed in dimethyl sulphoxide, in the presence of analkali metal hydride such as sodium hydride, at a temperature in theregion of 20° C., or in the presence of tetrabutylammonium bromide and abase such as an alkali metal hydroxide (for example sodium hydroxide,potassium hydroxide), in dimethyl sulphoxide, at a temperature ofbetween 20 and 100° C. The acetic acid treatment is performed at atemperature below 20° C.

The derivatives of formula R₂₀ --CO--COOR₁₀ in which R₁₀ and R₂₀ havethe same meanings as in the formula (I) are commercially available ormay be obtained by application or adaptation of the methods described byL. A. CARPINO, J. Org. Chem., 29, 2820 (1964) and H. H. WASSERMAN, J.Org. Chem., 50, 3573 (1985).

The compounds of formula (I) for which R represents a C═R₇ radical andR₇ represents a C(CONR₁₀ R₂₁)R₂₀ radical may be prepared by the actionof a corresponding compound of formula (I) for which R represents a C═R₇radical and R₇ represents a C(COOR₁₀)R₂₀ radical on an amine HNR₁₀ R₂₁in which R₁₀ and R₂₁ have the same meanings as in the formula (I).

When the acid is employed, the reaction is performed in the presence ofa condensing agent used in peptide chemistry, such as a carbodiimide(for example N,N'-dicyclohexylcarbodiimide) or N,N'-carbonyldiimidazole,in an inert solvent such as an ether (for example tetrahydrofuran,dioxane), an amide (dimethylformamide) or a chlorinated solvent (forexample methylene chloride, 1,2-dichloroethane, chloroform), at atemperature between 0° C. and the refluxing temperature of the reactionmixture. When an ester is employed, the reaction is then performedeither in an organic medium, optionally in the presence of an acceptorfor acid such as a nitrogenous organic base (for example trialkylamine,pyridine, 1,8-diazabicyclo 5.4.0!undec-7-ene or 1,5-diazabicyclo4.3.0!non-5-ene), in a solvent such as is mentioned above, or a mixtureof these solvents, at a temperature between 0° C. and the refluxingtemperature of the reaction mixture, or in a two-phase aqueous-organicmedium in the presence of an alkali metal base or alkaline-earth metalbase (sodium hydroxide, potassium hydroxide) or an alkali metalcarbonate or bicarbonate or alkaline-earth metal carbonate orbicarbonate, at a temperature of between 0 and 40° C.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical,R₄ represents an alkyl or -alk-Het radical or a phenylalkyl radical inwhich the phenyl ring is optionally substituted with one or moresubstituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino,hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals and R₅ isidentical to R₄ may be prepared by the action of a correspondingcompound of formula (I) for which R represents a CH--R₆ radical and R₆represents a hydrogen atom on a halide of formula Hal-Ri in which Rirepresents an alkyl or -alk-Het radical or a phenylalkyl radical inwhich the phenyl ring is optionally substituted with one or moresubstituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino,hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals, alk, Hetand R₁₀ having the same meanings as in the formula (I).

This reaction is preferably performed in an inert solvent such asdimethyl sulphoxide, dimethylformamide, tetrahydrofuran or dioxane, inthe presence of a base such as an alkali metal hydroxide (for examplesodium hydroxide, potassium hydroxide), optionally in the presence oftetrabutylammonium bromide in dimethyl sulphoxide or in the presence ofan alkali metal hydride (for example sodium hydride), at a temperaturebetween 20° C. and the boiling point of the reaction medium.

The derivatives Hal-Ri are commercially available or may be obtainedfrom the corresponding alcohols by application or adaptation of themethods described by R. C. LAROCK, "Comprehensive OrganicTransformations", Ed. VCH, page 353 (1989).

The compounds of formula (I) for which R represents a C(R₄)R₅ radical,R₄ represents an alkyl or -alk-Het radical or a phenylalkyl radical inwhich the phenyl ring is optionally substituted and R₅ represents analkyl (1-11C in an unbranched or branched chain), -alk-CN, -alk-Het,-alk-NR₁₀ R₁₈, -alk-COOR₁₀, -alk-CO--NR₁₀ R₁₈ or --COOR₁₀ radical or aphenylalkyl radical in which the phenyl ring is optionally substituted,or alternatively R represents a CH--R₆ radical and R₆ represents an--NR₁₄ R₁₅ or -alk-NR₁₄ R₁₅ radical, in which radicals R₁₄ and R₁₅,which may be identical or different, each represent an alkyl radical oralternatively R₁₄ represents a hydrogen atom and R₁₅ represents analkyl, --COR₂₂ or --SO₂ R₂₄ radical, R₂₂ represents an alkyl,cycloalkyl, --COOalk, -alk-COOR₁₀ or optionally substituted phenylradical, a phenylalkyl radical in which the phenyl ring is optionallysubstituted or an --OR₁₇, -Het, -alk-Het or -alk-NR₁₀ R₁₂ radical andR₂₄ represents an alkyl or phenyl radical, may be prepared by the actionof a corresponding compound of formula (I) for which R represents aCH--R₆ radical and R₆ represents an alkyl or -alk-Het radical or aphenylalkyl radical in which the phenyl ring is optionally substitutedwith one or more substituents chosen from halogen atoms and alkyl,alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and-alk-COOR₁₀ radicals, or R represents a CH--R₆ radical, R₆ represents an--NR₁₄ Rl₅ or -alk-NR₁₄ R₁₅ radical and R₁₄ and R₁₅ each represent ahydrogen atom, on a halide Hal-Rj for which Rj represents an alkyl(1-11C in an unbranched or branched chain), -alk-CN, -alk-Het, -alk-NR₁₀R₁₈, -alk-COOR₁₀, -alk-CO--NR₁₀ R₁₈ or --COOR₁₀ radical, a phenylalkylradical in which the phenyl ring is optionally substituted with one ormore substituents chosen from halogen atoms and alkyl, alkoxy, nitro,amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals, ora --COR₂₂ or --SO₂ R₂₄ radical, R₂₂ represents an alkyl, cycloalkyl,--COOalk or -alk-COOR₁₀ radical, a phenyl radical optionally substitutedwith one or more substituents chosen from halogen atoms and alkyl,alkoxy, nitro, amino, hydroxyl, -alk-NH₂, --COOR₁₀, cyano and-alk-COOR₁₀ radicals, a phenylalkyl radical in which the phenyl ring isoptionally substituted with one or more substituents chosen from halogenatoms and alkyl, alkoxy, nitro, amino, hydroxyl, -alk-NH₂, --COOR₁ O,cyano and -alk-COOR₁₀ radicals, or an --OR₁₇₁ -Het, -alk-Het or-alk-NR₁₀ R₁₂ radical and R₂₄ represents an alkyl or phenyl radical,alk, Het and R₁₀ having the same meanings as in the formula (I),followed, for the compounds for which R₅ represents an -alk-COOR₁₀ or--COOR₁₀ radical in which radicals R₁₀ is a hydrogen atom, by ahydrolysis of the compound for which R₅ represents a --COOR₁₀ radicaland R₁₀ is an alkyl radical.

This reaction is preferably performed in an inert solvent such asdimethyl sulphoxide, dimethylformamide, tetrahydrofuran or dioxane, inthe presence of a base such as an alkali metal hydroxide (for examplesodium hydroxide, potassium hydroxide), optionally in the presence oftetrabutylammonium bromide in dimethyl sulphoxide or in the presence ofan alkali metal hydride (for example sodium hydride), at a temperaturebetween 20° C. and the boiling point of the reaction medium. Thehydrolysis is preferably performed by means of a base such as an alkalimetal hydroxide (for example sodium hydroxide or potassium hydroxide),in a water/alcohol (for example ethanol) mixture, at a temperature ofapproximately 20 to 30° C.

The derivatives Hal-Rj are commercially available, or those for which Rjrepresents an -alk-CO--NR₁₀ R₁₈ radical may be prepared by the action ofan amine HNR₁₀ R₁₈ on a derivative Hal-alk-CO-Hal in which Halrepresents a halogen atom and alk represents an alkyl radical, in aninert solvent such as dimethylformamide, tetrahydrofuran or achlorinated solvent, in the presence of an organic base such as atrialkylamine or pyridine, at a temperature between 0° C. and theboiling point of the reaction medium. The derivatives Hal-alk-CO-Hal arecommercially available or may be obtained by halogenation of thecorresponding carboxylic acids by means of a halogenating agent such asthionyl chloride, in an inert solvent such as 1,2-dichloroethane, at atemperature in the region of 60° C. The acids Hal-alk-COOH may beobtained by the action of an alkali metal cyanide on a derivativeHal-alk-Hal in which alk represents an alkyl radical and Hal representsa halogen atom, in a water/alcohol mixture, at a temperature between 0°C. and the boiling point of the reaction medium, followed by the actionof a strong acid such as hydrochloric acid, in an aqueous medium, at atemperature between 0° C. and the boiling point of the reaction medium.The derivatives Hal-COOR₁₀ are commercially available or may be obtainedby application or adaptation of the methods described in HOUBEN-WEYL,volume 8, page 102 (1952). Those for which Rj represents a --COR₂₂radical may be obtained from the corresponding carboxylic acids byapplication or adaptation of the methods described by B. HELFERICH etal., Organic Synth., I, 147; R. ADAMS et al., Organic Synth., I, 304 andJ. GASON, Organic Synth., III, 169, and those for which Rj represents an--SO₂ R₂₄ radical may be obtained from the corresponding sulphonic acidsby reacting a halogenated derivative of phosphorus (for example PCl₅,POCl₃) or thionyl chloride, in an aqueous phase or in an inert solvent(for example dichloromethane, at a temperature of between 20 and 40° C.

The compounds of formula (I) for which R represents a C(R₄)R₅ radicaland R₄ and R₅, with the carbon atom to which they are attached, form acycloalkyl radical may be prepared by the action of a correspondingcompound of formula (I) for which R represents a CH--R₆ radical and R₆represents a hydrogen atom on a derivative of formula Hal-alk-Hal inwhich Hal represents a halogen atom and alk represents an alkyl (2-5C)radical.

This reaction is preferably performed in an inert solvent such asdimethyl sulphoxide, dimethylformamide, tetrahydrofuran or dioxane, inthe presence of a base such as an alkali metal hydroxide (for examplesodium hydroxide, potassium hydroxide), optionally in the presence oftetrabutylammonium bromide in dimethyl sulphoxide or in the presence ofan alkali metal hydride (for example sodium hydride), at a temperaturebetween 20° C. and the boiling point of the reaction medium.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an --NR₈ R₉ radical and R₈ and R₉ represent hydrogenatoms may be prepared by the action of a halide Hal-R₄ in which Halrepresents a halogen atom and R₄ has the same meanings as in the formula(I) on a corresponding compound of formula (I) for which R represents aCH--R₆ radical, R₆ represents an --NR₁₄ R₁₅ radical, R₁₄ represents ahydrogen atom, R₁₅ represents a --COR₂₂ radical and R₂₂ represents analkyl (1C) radical, followed by a hydrolysis.

This reaction is generally performed in an inert solvent such asdimethyl sulphoxide, in the presence of an alkali metal hydride such assodium hydride, at a temperature in the region of 20° C. The hydrolysisis generally performed by means of an inorganic acid such ashydrochloric acid, in an aqueous medium, at the boiling point of thereaction medium.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an --NR₈ R₉ radical, R₉ represents a hydrogen atomand R₈ represents an alkyl, -alk-COOR₁₀, -alk-NR₁₀ R₂₁ or -alk-Hetradical or a phenylalkyl radical in which the phenyl ring is optionallysubstituted may be prepared by the action of a corresponding compound offormula (I) for which R represents a C(R₄)R₅ radical, R₅ represents an--NR₈ R₉ radical and R₈ and R₉ represent hydrogen atoms on a halideHal-R₈ in which R₈ has the same meanings as above.

This reaction is generally performed in an inert solvent such asdimethylformamide, in the presence of an alkali metal carbonate such assodium or potassium carbonate or a trialkylamine such as triethylamineor pyridine, at a temperature between 0° C. and the boiling point of thereaction medium.

The halides Hal-R₈ are commercially available, or those for which R₈represents an -alk-NR₁₀ R₂₁ radical may be obtained by the action of theamine HNR₁₀ R₂₁ in which R₁₀ and R₂₁ have the same meanings as in theformula (I) on a halide Hal-alk-Hal in which Hal represents a halogenatom and alk represents an alkyl radical, in an inert solvent such asdimethylformamide, in the presence of an acceptor for acid such as anitrogenous base, at a temperature of between 0 and 25° C. Those forwhich R₈ represents an -alk-COOR₁₀ radical may be obtained by the actionof a derivative Hal-alk-Hal in which Hal represents a halogen atom andalk represents an alkyl radical on an alkali metal cyanide (sodium orpotassium cyanide), in a water/alcohol mixture, at a temperature between0° C. and the boiling point of the reaction medium, followed by theaction of a strong acid such as HCl, optionally in the presence of analcohol, at a temperature between 0° C. and the boiling point of thereaction medium.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an --NR₈ R₉ radical, R₈ has the same meanings as inthe formula (I) and R₉ represents an alkyl radical may also be preparedby the action of a corresponding compound of formula (I) for which Rrepresents a C(R₄)R₅ radical, R₅ represents an --NR₈ R₉ radical, R₈ hasthe same meanings as in the formula (I) and R₉ represents a hydrogenatom on a derivative of formula Hal-R₉ in which Hal represents a halogenatom and R₉ represents an alkyl radical.

This reaction is performed in an inert solvent such asdimethylformamide, in the presence of an acceptor for acid such as anitrogenous organic base (pyridine or trialkylamine such astriethylamine), at a temperature between 0° C. and the boiling point ofthe reaction medium.

The derivatives Hal-R₉ are commercially available or may be obtained byapplication or adaptation of the methods described by C. LAROCK,"Comprehensive Organic Transformations", Ed. VCH, pages 345 and 353(1989).

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an -alk-COOR₁₀ radical may be prepared by the actionof a corresponding compound of formula (I) for which R represents aCH--R₆ radical, R₆ represents an -alk-COOR₁₀ radical and R₁₀ has thesame meanings as in the formula (I) on a halide Hal-R₄ in which R₄ hasthe same meanings as in the formula (I).

This reaction is performed in an inert solvent such asdimethylformamide, in the presence of an alkali metal hydride such assodium or potassium hydride, at a temperature in the region of 20° C.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an -alk(2-6C)OH radical may be prepared by theaction of (COCl)₂ on a corresponding compound of formula (I) for which Rrepresents a C(R₄)R₅ radical in which R₅ represents an -alk-COOR₁₀radical and R₁₀ represents a hydrogen atom, followed by a reduction.

This reaction is performed in an inert solvent such as dioxane. Thereduction is preferably performed by means of sodium borohydride, in aninert solvent such as dimethylformamide, at a temperature of between 10and 20° C.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an -alk(1C)OH radical may be prepared by the actionof trimethylsilane chloride on a corresponding compound of formula (I)for which R represents a CH--R₆ radical and R₆ represents an alkyl or-alk-Het radical or a phenylalkyl radical in which the phenyl ring isoptionally substituted with one or more substituents chosen from halogenatoms and alkyl, alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂,--COOR₁₀ and -alk-COOR₁₀ radicals, and then of trioxane.

This reaction is generally performed in an inert solvent such asdimethylformamide, in the presence of sodium hydride, followed byreaction with trioxane at a temperature of between 0 and 25° C.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an --NH--CHO radical, or R represents a CH--R₆radical and R₆ represents an --NH--CHO radical, may be prepared by theaction of a corresponding compound of formula (I) for which R representsa C(R₄)R₅ radical in which R₅ represents an --NR₈ R₉ radical, R₈ and R₉being hydrogen atoms, or R represents a CH--R₆ radical, R₆ represents an--NR₁₄ R₁₅ radical and R₁₄ and R₁₅ represent hydrogen atoms, on CH₃COOCHO.

This reaction is preferably performed in an inert solvent such as formicacid, in the presence of sodium acetate, at a temperature in the regionof 20° C.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an --NH--COOR₁₇, --NH--CO-Het, --NH--CO-alk-COOR₁₀or --NH--CO-alk--NR₁₀ R₁₈ radical, an --NH--CO--Ar radical in which Aris optionally substituted, an --NH--CO-alk-Ar radical in which Ar isoptionally substituted or an --NH-SO₂ --R₂₄, --NH--CO-alk-Het,--NH--CO-alk or --NH--CO-cycloalkyl radical, or R represents CH--R₆, R₆represents an --NR₁₄ R₁₅ radical, R₁₄ represents a hydrogen atom, R₁₅represents a --COR₂₂ radical and R₂₂ represents an --OR₁₇, -Het,-alk-COOR₁₀ or -alk-NR₁₀ R₁₂ radical, an -alk-Ar radical in which Ar isoptionally substituted, an -alk-Het radical or a phenyl radicaloptionally substituted with one or more substituents chosen from halogenatoms and alkyl, alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂,--COOR₁₀ and -alk-COOR₁₀ radicals, may be prepared by the action of acorresponding compound of formula (I) for which R represents a C(R₄)R₅radical, R₅ represents an --NR₈ R₉ radical and R₈ and R₉ representhydrogen atoms, or R represents a CH--R₆ radical, R₆ represents an--NR₁₄ R₁₅ radical, R₁₄ represents a hydrogen atom and R₁₅ represents ahydrogen atom, on a derivative Hal-Rk in which Hal represents a halogenatom and Rk represents a --COOR₁₇, --CO-Het, --CO-alk-COOR₁₀,--CO-alk-NR₁₀ R₁₈ or --CO-alk-NR₁₀ R₁₂ radical, a --CO-alk-Ar radical inwhich Ar is optionally substituted with one or more substituents chosenfrom halogen atoms and alkyl, alkoxy, nitro, amino, hydroxyl, cyano,-alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals, a --CO-alk-Het, --SO₂ --R₂₄or --CO-alk-Het radical, a --CO--Ar radical in which Ar is optionallysubstituted with one or more substituents chosen from halogen atoms andalkyl, alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and-alk-COOR₁₀ radicals, or a --CO-alk or --CO--cycloalkyl radical, R₇,R₁₀, R₁₂, R₁₇, R₁₈, R₂₄, Het, Ar and alk having the same meanings as inthe formula (I).

This reaction is generally performed in an inert solvent such asdimethylformamide or dimethyl sulphoxide, in the presence of an acceptorfor acid such as a trialkylamine (for example triethylamine) or analkali metal hydride (for example sodium hydride) at a temperature inthe region of 20° C.

The derivatives Hal-Rk are commercially available or those for which Rkrepresents a --CO-Het, --CO-alk-Het, --CO-cycloalkyl, --CO-alk-COOR₁₀ or--CO-alk-NR₁₀ R₁₈ radical or a --CO-alk-Ar radical in which Ar isoptionally substituted with one or more substituents chosen from halogenatoms and alkyl, alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂,--COOR₁₀ and -alk-COOR₁₀ radicals may be obtained from the correspondingcarboxylic acids by the action of a phosphorus halide (for example PCl₅or POCl₃), preferably in the phosphorus halide, optionally in thepresence of an inert solvent such as dichloromethane, at a temperaturebetween 20° C. and the boiling point of the reaction medium, or byapplication or adaptation of the methods described by R. HELPER et al.,Organic Synth., I, 147 and R. ADAMS et al., Organic Synth., I, 394 andJ. CASON, Organic Synth., III, 169.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an --NH--CO-Het, --NH--CO-alk-COOR₁₀ or--NH--CO-alk-NR₁₀ R₁₈ radical, an --NH--CO--Ar radical in which Ar isoptionally substituted, an --NH--CO-alk-Ar radical in which Ar isoptionally substituted, or an --NH--CO-alk-Het, --NH--CO-alk or--NH--CO-cycloalkyl radical, or R represents a CH--R₆ radical, R₆represents an --NR₁₄ R₁₅ radical, R₁₄ represents a hydrogen atom, R₁₅represents a --COR₂₂ radical and R₂₂ represents a -Het, -alk-COOR₁₀ or-alk-NR₁₀ R₁₂ radical, a phenylalkyl radical in which the phenyl isoptionally substituted, an -alk-Het radical or an optionally substitutedphenyl radical, may also be prepared by the action of a compound offormula (I) in which R represents a C(R₄)R₅ radical, R₅ represents an--NR₈ R₉ radical and R₈ and R₉ represent hydrogen atoms, or R representsa CH--R₆ radical, R₆ represents an --NR₁₄ R₁₅ radical, R₁₄ represents ahydrogen atom and R₁₅ represents a hydrogen atom, on a derivative HO--RIin which RI represents a --CO-Het, --CO-alk-COOR₁₀, --CO-alk-NR₁₀ R₁₈ or--CO-alk-NRlOR₁₂ radical, a --CO-alk-Ar radical in which Ar isoptionally substituted with one or more substituents chosen from halogenatoms and alkyl, alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂,--COOR₁₀ and -alk-COOR₁₀ radicals, a --CO-alk-Het radical, a --CO--Arradical in which Ar is optionally substituted with one or moresubstituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino,hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals, or a--CO-alk or --CO-cycloalkyl radical, R₁₀, R₁₂, R₁₈, Het, Ar and alkhaving the same meanings as in the formula (I).

This reaction is generally performed in an inert solvent such asdimethylformamide, in the presence of hydroxybenzotriazole,1-(3-dimethylaminopropyl)-3-ethylcabodiimide and an organic base such asa trialkylamine (for example triethylamine), at a temperature of between0° C. and 5° C.

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents a 1-pyrrolyl radical optionally substituted with a--COOR₁₀ radical, or R represents a CH--R₆ radical and R₆ represents a1-pyrrolyl radical optionally substituted with a --COOR₁₀ radical, maybe prepared by the action of a corresponding compound of formula (I) forwhich R represents a C(R₄)R₅ radical in which R₅ represents an --NR₈ R₉radical and R₈ and R₉ represent hydrogen atoms, or R represents a CH--R₆radical, R₆ represents an --NR₁₄ R₁₅ radical and R₁₄ and R₁₅ representhydrogen atoms, on a derivative of formula: ##STR6## in which alkrepresents an alkyl radical, Rm represents a hydrogen atom or a --COOR₁₀radical and R₁₀ has the same meanings as in the formula (I).

This reaction is generally performed in an inert solvent such as aceticacid, at the boiling point of the reaction medium, optionally in thepresence of an acceptor for acids such as sodium acetate.

The derivatives of formula (V) may be obtained by application oradaptation of the methods described by J. FAKSTORP et al., J. Am. Chem.Soc., 72, 869 (1950), N. CLAUSON-KAAS et al., Acta Chem. Scan., 6, 551(1952) and STIBOR et al., Collect. Czech. Chem. Commun., 47 (12), 3261(1992).

The compounds of formula (I) for which R represents a C(R₄)R₅ radical inwhich R₅ represents an --NH--CO--NH-alk-Ar radical in which Ar isoptionally substituted, an --NH--CO--NH-Het or --NH--CO--NH-alk-Hetradical, an --NH--CO--NH--Ar radical in which Ar is optionallysubstituted, or an --NH--CO--NH-alk or --NH--CO--NH2 radical, or Rrepresents a CH--R₆ radical and R₆ represents an --NR₁₄ R₁₅ or -alk-NR₁₄R₁₅ radical in which radicals R₁₄ represents a hydrogen atom, R₁₅represents a --COR₂₂ or --CSR₂₃ radical, R₂₂ represents an --NH-alk or--NH₂ radical, an --NH--Ar radical in which Ar is optionallysubstituted, an --NH-alk-Ar radical in which Ar is optionallysubstituted, or an --NH-alk-Het or --NH-Het radical and R₂₃ representsan --NH-alk, --NH₂, --NH--Ar or --NH-Het radical, may be prepared by theaction of a corresponding compound of formula (I) for which R representsa C(R₄)R₅ radical, R₅ represents an --NR₈ R₉ radical and R₈ and R₉represent hydrogen atoms, or R represents a CH--R₆ radical and R₆represents an --NR₁₄ R₁₅ or -alk-NR₁₄ R₁₅ radical in which radicals R₁₄and R₁₅ each represent a hydrogen atom, on a derivative Rn═C═N--Ro inwhich Rn represents a trimethylsilyl, alkyl or -Het radical, aphenylalkyl radical in which the phenyl is optionally substituted withone or more substituents chosen from halogen atoms and alkyl, alkoxy,nitro, amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀radicals, an -alk-Het radical or a phenyl radical optionally substitutedwith one or more substituents chosen from halogen atoms and alkyl,alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and-alk-COOR₁₀ radicals in which radicals R₁₀ alk, Ar and Het have the samemeanings as in the formula (I) and Ro represents an oxygen or sulphuratom, optionally followed by a hydrolysis.

This reaction is generally performed in an inert solvent such asdimethylformamide, tetrahydrofuran or dioxane, at a temperature between20° C. and the boiling point of the reaction medium. For the compoundsfor which R₅ represents an --NH--CO--NH₂ radical or R₂₂ and R₂₃ are NH₂radicals, this reaction is followed by a hydrolysis of the silylderivative previously obtained by means of an aqueous solution, at atemperature of between 20 and 50° C.

The derivatives Rn--N═C═Ro may be obtained from the correspondingprimary amines by the action of phosgene or thiophosgene, by applicationor adaptation of the methods described by R. L. SHRINER et al., OrganicSynth., II, 453 and G. M. DYSON, Organic Synth., I, 165; R. J. SLOCOMPIEet al., J. Am. Chem. Soc., 72, 1888 (1950) and S. PATAI, "The chemistryof cyanates and their thio derivatives", Ed. John Wiley and Sons, pages619 and 819 (1977).

The corresponding primary amines are commercially available, or thosefor which Rp represents an optionally substituted phenyl or Het radicalmay be obtained by application or adaptation of the methods described byB. A. TERTOV et al., Khim. Geterotsikl. Soedin, II, 1552 (1972) and R.C. LAROCK, "Comprehensive Organic Transformations", Ed. VCH, page 399,which consists in reacting the organolithium or organomagnesiumderivative of the heterocycle or of the optionally substituted benzenewith PhN₃, in the presence of acetic acid, NH₂ OCH₃, (PhO)₂ PON₃ or N₃CH₂ Si (CH₃)₃. The organolithium or organomagnesium derivatives may beobtained by application or adaptation of the methods described by D. L.COMINS et al., J. Org. Chem., 52, 104 (1987); N. FURUKANA et al.,Tetrahedron Lett., 28 (47), 5845 (1987); A. R. KATRITZKY et al., Org.Prep. Procedure Int., 20 (6), 585 (1988), A. J. CLARKE et al.,Tetrahedron Lett., 27, 2373 (1974) and A. W. GSCHWEN et al., OrganicReaction, 26, 1 (1979). The amines for which Rp represents an -alk-Hetradical or an -alk-Ar radical in which Ar is optionally substituted arecommercially available or are obtained from the corresponding halides bythe action of NaN(SiCH₃)₃ or of the potassium salt of phthalimide, in aninert solvent such as dimethylformamide, in the presence of an organicbase such as a trialkylamine or pyridine, at a temperature between 0° C.and the boiling point of the reaction medium, followed by a hydrolysis,either in an acid medium (for example HCl) at a temperature between 20°C. and the boiling point of the reaction medium, or by means ofhydrazine, in a lower aliphatic alcohol, at the boiling point of thereaction medium. The derivatives H₂ N-alk-Ar in which Ar is optionallysubstituted may also be obtained by application or adaptation of themethods described by J. F. KING et al., J. Am. Chem. Soc., 114, 3028(1992); B. M. ADGER et al., Tetrahedron Lett., 25 (45), 5219 (1984); R.SCARPATI et al., Gazz. Chim. Ital., 97 (5), 654 (1967).

The compounds of formula (I) for which R represents a CH--R₆ radical inwhich R₆ represents a hydroxyl radical may be prepared by reducing acorresponding compound of formula (I) for which R represents a C═R₇radical and R₇ represents an oxygen atom.

This reaction is preferably performed in an inert solvent such as analcohol (for example methanol, ethanol), in the presence of sodiumborohydride, at a temperature of between 15 and 40° C.

The compounds of formula (I) for which R represents a CH--R₆ radical inwhich R₆ represents an alkyl (2-11C) radical, a phenylalkyl radical inwhich the phenyl ring is optionally substituted with one or moresubstituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino,hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals, or an-alk-COOR₁₀ or -alk-Het radical may be prepared by hydrogenation of aderivative of formula: ##STR7## in which R₁, R₂ and R₃ have the samemeanings as in the formula (I), Rp represents an unbranched- orbranched-chain alkyl radical containing 1 to 10 carbon atoms, a phenylradical optionally substituted with one or more substituents chosen fromhalogen atoms and alkyl, alkoxy, nitro, amino, hydroxyl, cyano,-alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals, a phenylalkyl (1-5C)radical in which the phenyl ring is optionally substituted with one ormore substituents chosen from halogen atoms and alkyl, alkoxy, nitro,amino, hydroxyl, cyano, -alk-NH₂, --COOR₁₀ and -alk-COOR₁₀ radicals, ora --COOR₁₀, -alk(1-5C)--COOR₁₀, -Het or -alk(1-5C)-Het radical in whichradicals alk, Het and R₁₀ have the same meanings as in the formula (I)and alk represents an alkyl radical, optionally followed by asaponification of the compounds for which R₆ is an -alk-COOR₁₀ radicaland R₁₀ is an alkyl radical, to obtain the compounds for which R₆ is an-alk-COOR₁₀ radical and R₁₀ is a hydrogen atom.

This reduction is performed by means of hydrogen at a pressure of 1 to20 bar, in the presence of a hydrogenation catalyst such as palladinizedcharcoal, palladium hydroxide or palladium (N. RICO et al., NouveauJournal de Chimie, 10, 1, 25 (1986)), in an inert solvent such asdimethylformamide, acetic acid, ethyl acetate, an alcohol (for examplemethanol or ethanol) or a mixture of these solvents, at a temperature ofbetween 20 and 60° C., or by adaptation of the method of L. M. STRAWN etal., J. Med. Chem., 32, 2104 (1989), which consists in reacting theethylenic derivative with hydroxylamine sulphate and H₂ NOSO₃ H, in anaqueous medium, at a pH of between 6 and 7, at a temperature of 10° C.The saponification is performed by any known method, and preferably bymeans of an acid such as hydrochloric acid, in an alcohol such asethanol, at a temperature of 20 to 60° C., or by means oftrifluoroacetic acid at a temperature in the region of 20 to 60° C.

The derivatives of formula (VI) for which Rp represents an unbranched-or branched-chain alkyl radical containing 5 to 10 carbon atoms may beprepared as described above for their homologues (compounds of formula(I) for which R represents a C═R₇ radical, R₇ represents a --CH--R₁₉radical and R₁₉ represents an alkyl radical).

The derivatives of formula (VI) for which Rp represents a --COOR₁₀radical in which Rio represents an alkyl radical may be obtained by theaction of a corresponding compound of formula (I) for which R representsa CH--R₆ radical and R₆ represents a hydrogen atom on an alkylglyoxalate. This reaction is performed in an inert solvent such asdimethyl sulphoxide, in the presence of an alkali metal hydride (forexample sodium or potassium hydride), at a temperature in the region of20° C.

The compounds of formula (I) for which R represents a CH--R₆ radical inwhich R₆ represents a methyl radical may also be prepared by reductionof the corresponding compounds of formula (I) for which R represents aC═R₇ radical, R₇ represents a CH--R₁₉ radical and R₁₉ represents ahydroxyl or --NR₂₅ R₂₆ radical.

This reduction is generally performed by means of hydrogen, under apressure of 1 to 50 bar, in an inert solvent such as dimethylformamide,acetic acid, ethyl acetate, an alcohol (for example methanol, ethanol)or a mixture of these solvents, in the presence of a hydrogenationcatalyst such as palladinized charcoal or palladium hydroxide, at atemperature of between 20° C. and 60° C.

The compounds of formula (I) for which R represents a CH--R₆ radical andR₆ represents an -alk(1C)--OH radical may be prepared by reduction ofthe corresponding compounds of formula (I) for which R represents a C═R₇radical, R₇ represents a CH--R₁₉ radical and R₁₉ represents a hydroxylradical.

This reduction is generally performed using reducing agents such assodium borohydride, in an inert solvent such as an alcohol (for examplemethanol, ethanol), at a temperature in the region of 20° C.

The compounds of formula (I) for which R represents a CH--R₆ radical andR₆ represents an -alk(2-6C)--OH radical may be prepared by reduction ofa derivative of formula (VI) in which R₁, R₂ and R₃ have the samemeanings as in the formula (I) and Rp represents an -alk(1-5C)--O--CH₂--Ar radical, alk and Ar having the same meanings as in the formula (I).

This reduction is preferably performed by means of hydrogen, under apressure of 1 to 50 bar, in the presence of a catalyst such aspalladinized charcoal or palladium hydroxide, in an inert solvent suchas dimethylformamide, acetic acid, an alcohol or ethyl acetate, at atemperature of between 20 and 60° C.

The derivatives of formula (VI) for which Rp represents an-alk(1-5C)--O--CH₂ --Ar radical may be obtained by the action of acorresponding compound of formula (I) for which R represents a CH--R₆radical and R₆ represents a hydrogen atom on an aldehydeOHC-alk(1-5C)--O--CH₂ --Ar.

This reaction is performed under the same conditions as those mentionedabove for the preparation of the compounds of formula (I) for which Rrepresents a C═R₇ radical, R₇ represents a CH--R₁₉ radical and R₁₉represents an alkyl radical.

The derivatives OHC-alk(1-5C)--O--CH₂ --Ar may be obtained byapplication or adaptation of the methods described by P. SCHORIGIN etal., Chem. Ber., 68, 838 (1935) and A. GAIFFE et al., C. R. Acad. Sc.Paris, Ser. C. 266, 1379 (1968).

The compounds of formula (I) for which R represents a CH--R₆ radical inwhich R₆ represents an --NR14R₁₅ radical and R₁₄ and R₁₅ each representa hydrogen atom may be prepared by hydrolysis of a correspondingcompound of formula (I) for which R represents a CH--R₆ radical in whichR₆ represents an --NR₁₄ R₁₅ radical, R₁₄ represents a hydrogen atom, R₁₅represents a --COR₂₂ radical and R₂₂ represents an alkyl radical.

This hydrolysis is generally performed by means of an acid such ashydrochloric acid, in an aqueous medium, at the boiling point of thereaction medium.

The compounds of formula (I) for which R represents a CH--R₆ radical inwhich R₆ represents an --NR₁₄ R₁₅ radical, R₁₄ represents a hydrogenatom, R₁₅ represents a --COR₂₂ radical and R₂₂ represents an alkylradical may be prepared by the action of a reducing agent on acorresponding compound of formula (I) for which R represents a C═R₇radical and R₇ represents an NOH radical, followed by treatment with ananhydride (RqCO)₂ O for which Rq represents an alkyl radical.

This reaction is generally performed at a temperature of between 50 and100° C. As a reducing agent, zinc is preferably used.

The compounds of formula (I) for which R represents a CH--R₆ radical andR₆ represents an --NR₁₄ R₁₅ or -alk-NR₁₄ R₁₅ radical in which radicalsR₁₄ and R₁₅, which may be identical or different, each represent analkyl radical may be prepared by the action of a corresponding compoundof formula (I) for which R represents a CH--R₆ radical, R₆ represents an--NR₁₄ R₁₅ or -alk-NR₁₄ R₁₅ radical, R₁₄ represents a hydrogen atom andR₁₅ represents an alkyl radical on a halide of formula Hal-Rr in whichRr represents an alkyl radical.

This reaction is preferably performed in an inert solvent such asdimethylformamide, tetrahydrofuran or dimethyl sulphoxide, in thepresence of a base such as a tertiary amine (for example triethylamine)or aromatic amine (for example pyridine) or an inorganic base such as analkali metal hydroxide (for example sodium hydroxide, potassiumhydroxide), at a temperature between 20° C. and the boiling point of thereaction medium.

The compounds of formula (I) for which R represents a CH--R₆ radical andR₆ represents an --NR₁₄ R₁₅ or -alk-NR₁₄ R₁₅ radical in which radicalsR₁₄ represents a hydrogen atom, R₁₅ represents a --COR₂₂ radical and R₂₂represents an -alk-NR₁₀ R₁₂ radical in which R₁₀ and R₁₂ representhydrogen atoms and alk contains 1 carbon atom may be prepared by theaction of a corresponding compound of formula (I) for which R representsa CH--R₆ radical, R₆ represents an --NR₁₄ R₁₅ or -alk-NR₁₄ R₁₅ radicaland R₁₄ and R₁₅ each represent a hydrogen atom on an acid HOOC--CH₂--NH--Rs in which Rs represents a group protecting the amine function,such as tert-butoxycarbonyl, followed by a hydrolysis.

This reaction is preferably performed in an inert solvent such asdimethylformamide, in the presence of hydroxybenzotriazole,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and an organic base suchas a trialkylamine (for example triethylamine), at a temperature ofbetween 0 and 5° C. The hydrolysis is generally performed by means oftrifluoroacetic acid at a temperature in the region of 20° C.

The compounds of formula (I) in which R represents a CH--R₆ radical, R₆represents an -alk-NR₁₄ R₁₅ radical and R₁₄ and R₁₅ each represent ahydrogen atom may be prepared by the action of bromine and sodiumhydroxide on a compound of formula (I) for which R represents a CH--R₆radical, R₆ represents an -alk-CO--NR₁₀ R₁₈ radical and R₁₀ and R₁₈represent hydrogen atoms.

This reaction is generally performed in an aqueous medium at atemperature of between 20 and 70° C.

The compounds of formula (I) for which R represents a CH--R₆ radical andR₆ represents an -alk-CO--NR₁₀ R₁₈ radical may be prepared by the actionof a corresponding compound of formula (I) for which R represents aCH--R₆ radical and R₆ represents an -alk-COOR₁₀ radical on an amineHNR₁₀ R₁₈ in which R₁₀ and R₁₈ have the same meanings as in the formula(I).

When the acid is employed, the reaction is performed in the presence ofa condensing agent used in peptide chemistry, such as a carbodiimide(for example N,N'-dicyclohexylcarbodiimide) or N,N'-carbonyldiimidazole,in an inert solvent such as an ether (for example tetrahydrofuran,dioxane), an amide (dimethylformamide) or a chlorinated solvent (forexample methylene chloride, 1,2-dichloroethane, chloroform), at atemperature between 0° C. and the refluxing temperature of the reactionmixture. When an ester is employed, the reaction is then performedeither in an organic medium, optionally in the presence of an acceptorfor acid such as a nitrogenous organic base (for example trialkylamine,pyridine, 1,8-diazabicyclo 5.4.0!undec-7-ene or 1,5-diazabicyclo-4.3.0!non-5-ene), in a solvent as is mentioned above, or a mixture ofthese solvents, at a temperature between 0° C. and the refluxingtemperature of the reaction mixture, or in a two-phase aqueous-organicmedium in the presence of an alkali metal base or alkaline-earth metalbase (sodium hydroxide, potassium hydroxide) or an alkali metalcarbonate or bicarbonate or alkaline-earth metal carbonate orbicarbonate, at a temperature of between 0 and 40° C.

The amines HNR₁₀ R₁₈ are commercially available or may be obtained fromthe corresponding halides by application or adaptation of the methodsdescribed by R. C. LAROCK, "Comprehensive Organic Transformations", Ed.VCH, page 397 (1989).

The compounds of formula (I) for which R represents a CH--R₆ radical, R₆represents an -alk(lC)--CO--NR₁₀ R₁₈ radical and R₁₀ and R₁₈ representhydrogen atoms may also be prepared by hydrogenation of a derivative offormula (VI) in which R₁, R₂ and R₃ have the same meanings as in theformula (I) and Rp represents a --CONH₂ radical.

This reaction is generally performed either by means of hydrogen, in aninert solvent such as dimethylformamide, in the presence of ahydrogenation catalyst such as palladinized charcoal or palladium, at atemperature in the region of 20 to 30° C., or by adaptation of themethod of L. M. STRAWN et al., J. Med. Chem., 32, 2104 (1989), whichconsists in reacting the ethylenic derivative with hydroxylaminesulphate and H₂ NOSO₃ H, in an aqueous medium, at a pH of between 6 and7, at a temperature of 10° C.

The derivatives of formula (VI) in which R₁, R₂ and R₃ have the samemeanings as in the formula (I) and Rp represents a --CONH₂ radical maybe obtained by the action of ammonia on a corresponding compound offormula (VI) for which Rp represents a --COOR₁₀ radical in which R₁₀represents an alkyl radical, under the conditions described by D. I.MOWRY et al., Organic Synth., IV, 486 and J. KLEINBERG et al., OrganicSynth., IV, 516.

The compounds of formula (I) for which R represents a CH--R₆ radical andR₆ represents an --Rl₆ --COOR₁₀ radical may be prepared by the action ofa corresponding compound of formula (I) for which R represents a CH--R₆radical and R₆ represents a hydrogen atom on a derivative of formulaOHC-alk(0-5C)--COOR₁₀ in which R₁₀ has the same meanings as in theformula (I).

This reaction is preferably performed in an inert solvent such asdimethyl sulphoxide, in the presence of an alkali metal hydride such assodium hydride, at a temperature in the region of 20° C.

The derivatives of formula OHC-alk(0-5C) --COOR₁₀ may be obtained byapplication or adaptation of the method described by L. A. CARPINO, J.Org. Chem., 29, 2820 (1964).

The compounds of formula (I) for which R represents a CH--R₆ radical andR₆ represents a --CO--COOR₁₀ radical may be prepared by oxidation of acorresponding compound of formula (I) for which R represents a CH--R₆radical, R₆ represents an --Rl₆ --COOR₁₀ radical in which R₁₀ representsa hydrogen atom and R₁₆ represents a --CHOH-- radical, optionallyfollowed by an esterification.

This oxidation is preferably performed by means of potassiumpermanganate, in 3N sodium hydroxide solution, at a temperature in theregion of -3° C., or by means of platinum on charcoal, in 2N sodiumhydroxide solution, at a temperature of 70° C. The esterification ispreferably performed by means of an alcohol, in the presence of an acidsuch as hydrochloric or sulphuric acid, at the boiling point of thereaction medium.

The compounds of formula (I) for which R represents a CH--R₆ radical andR₆ represents a --COOalk radical may be prepared by the action of aninorganic acid on a derivative of formula: ##STR8## in which R₁, R₂ andR₃ have the same meanings as in the formula (I) and alk represents analkyl radical.

This reaction is generally performed in an inert solvent such astetrahydrofuran at a temperature of 0° C. As an inorganic acid,hydrochloric acid in 1N aqueous solution is preferably used.

The derivatives of formula (VII) may be obtained by the action of acorresponding compound of formula (I) for which R represents a CH--R₆radical and R₆ represents a hydrogen atom on a halide Hal-COOalk inwhich alk represents an alkyl radical.

This reaction is generally performed in an inert solvent such asdioxane, in the presence of an alkali metal hydride (for examplesodium), at a temperature between 20° C. and the boiling point of thereaction medium.

The derivatives Hal-COOalk are commercially available or may be obtainedby application or adaptation of the methods described in HOUBEN-WEYL,volume 8, page 108 (1952).

The compounds of formula (I) for which R₁ and possibly R₂ represent an--NH--CO--NR₁₁ R₁₂ or --NH--CS--NR₁₁ R₁₂ radical and R₁₂ represents ahydrogen atom may also be prepared by the action of a correspondingcompound of formula (I) for which R₁ represents an amino radical on aderivative Rx═C═N═Ry in which Rx represents an oxygen or sulphur atomand Ry represents a trimethylsilyl, alkyl, alkoxy, -alk-COOR₁₀, -alk-Hetor -alkNR₁₂ R₁₀ radical, a phenylalkyl radical in which the phenyl isoptionally substituted with one or more substituents chosen from halogenatoms and alkyl, alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂,--COOR₇ and -alk-COOR₇ radicals, a phenyl radical optionally substitutedwith one or more substituents chosen from halogen atoms and alkyl,alkoxy, nitro, amino, hydroxyl, cyano, -alk-NH₂, --COOR₇ and -alk-COOR₇radicals, or a Het radical in which radicals alk, Het, R₇, R₉, R₁₀ andR₁₂ have the same meanings as in the formula (I).

This reaction is generally performed in an inert solvent such asdimethylformamide, tetrahydrofuran or dioxane, at a temperature between20° C. and the boiling point of the reaction medium, followed by ahydrolysis of the silyl derivative to obtain the compound for which R₁₂represents a hydrogen atom, by means of an aqueous solution, at atemperature of between 20 and 50° C.

For a person skilled in the art, it is understood that, to carry out theprocesses described above according to the invention, it may benecessary to introduce groups protecting the amino, hydroxyl andcarboxyl functions in order to avoid side reactions. These groups arethe ones which make it possible for them to be removed without affectingthe remainder of the molecule. As examples of groups protecting theamino function, tert-butyl or methyl carbamate, which can be regeneratedby means of iodotrimethylsilane, may be mentioned. As examples of groupsprotecting the hydroxyl function, triethylsilyl and benzyl may bementioned. As groups protecting the carboxyl functions, esters (forexample methoxymethyl ester, tetrahydropyranyl ester, benzyl ester),oxazoles and 2-alkyl-1,3-oxazolines may be mentioned. Other usableprotective groups are described by W. GREENE et al., Protecting Groupsin Organic Synthesis, second edition, 1991, John Wiley & Sons.

The compounds of formula (I) may be purified by the usual known methods,for example by crystallization, chromatography or extraction.

The enantiomers of the compounds of formula (I) for which R represents aC(R₄)R₅ or CH--R₆ radical may be obtained by resolution of theracemates, for example by chiral-column chromatography according to W.H. PIRCKLE et al., asymmetric synthesis, vol. 1, Academic Press (1983)or by synthesis from chiral precursors.

The diastereoisomers of the compounds of formula (I) for which Rrepresents a C(R₄)R₅ or CH--R₆ radical containing one or more chiralcarbons, and the different E and Z isomers of the compounds of formula(I), may be separated by the usual known methods, for example bycrystallization or chromatography.

The compounds of formula (I) containing a basic residue can beoptionally converted to addition salts with an inorganic or organicacid, by the action of such an acid in an organic solvent such as analcohol, a ketone, an ether or a chlorinated solvent.

The compounds of formula (I) containing an acidic residue can optionallybe converted to metal salts or to addition salts with nitrogenous basesaccording to methods known per se. These salts may be obtained by theaction of a metal base (for example an alkali metal or alkaline-earthmetal base), ammonia, an amine or an amine salt on a compound of formula(I), in a solvent. The salt formed is separated by the usual methods.

These salts also form part of the invention.

As examples of pharmaceutically acceptable salts, there may be mentionedthe addition salts with inorganic or organic acids (such as acetate,propionate, succinate, benzoate, fumarate, maleate, oxalate,methanesulphonate, isethionate, theophyllineacetate, salicylate,methylenebis(β-hydroxynaphthoate, hydrochloride, sulphate, nitrate andphosphate), salts with alkali metals (sodium, potassium, lithium) orwith alkaline-earth metals (calcium, magnesium), the ammonium salt andthe salts of nitrogenous bases (ethanolamine, trimethylamine,methylamine, benzylamine, N-benzyl-β-phenethylamine, choline, arginine,leucine, lysine, N-methylglucamine).

The compounds of formula (I) possess advantageous pharmacologicalproperties. These compounds are antagonists of theα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor,also known by the name quisqualate receptor.

Moreover, the compounds of formula (I) are non-competitive antagonistsof the N-methyl-D-aspartate (NMDA) receptor and, more especially, theyare ligands for the glycine-modulating sites of the NMDA receptor.

These compounds are hence useful for treating or preventing allischaemias (such as focal or global ischaemia) following cerebrovascularaccidents, cardiac arrest, arterial hypotension, heart or lung surgeryor severe hypoglycaemia. They are also useful in the treatment of theeffects due to anoxia, either perinatal or following drowning orcerebrospinal lesions. These compounds may also be used for treating orpreventing the progression of neurodegenerative diseases, Huntington'schorea, Alzheimer's disease, amyotrophic lateral sclerosis,olivopontocerebellar atrophy and Parkinson's disease. These compoundsmay also be used for epileptogenic and/or convulsive manifestations, forthe treatment of cerebral or spinal trauma, trauma associated withdegeneration of the inner ear (R. PUJOL et al., Neuro report, 3, 299-302(1992)) or the retina (J. L. MONSINGER et al., Exp. Neurol., 113, 10-17(1991)), anxiety (KEHNE et al., Eur. J. Pharmacol., 193, 283 (1991)),depression (TRULLAS et al., Eur. J. Pharmacol., 185, 1 (1990)),schizophrenia (REYNOLDS, TIPS, 13, 116 (1992)), Tourette's syndrome andhepatic encephalopathies, as analgesics (DICKENSON et al., Neurosc.Letters, 121, 263 (1991)), anti-inflammatories (SLUTA et al., Neurosci.Letters, 149, 99-102 (1993)), antianorectics (SORRELS et al., BrainRes., 572, 265 (1992)), antimigraine drugs and antiemetics, and fortreating poisoning by neurotoxins or other substances which are NMDAreceptor agonists, as well as the neurological disorders associated withviral diseases such as AIDS (LIPTON et al., Neuron, 7, 111 (1991)),rabies, measles and tetanus (BAGETTA et al., Br. J. Pharmacol., 101, 776(1990)). These compounds are also useful for prevention of the symptomsof drug and alcohol abstinence and of the inhibition of opiate addictionand dependence. They may also be used in the treatment of defectsassociated with mitochondrial abnormalities such as mitochondrialmyopathy, Leber's syndrome, Wernicke's encephalopathy, Rett's syndrome,homocysteinaemia, hyperprolinaemia, hydroxybutiric/aminoaciduria,saturnine encephalopathy (chronic lead poisoning) and sulphite oxidasedeficiency.

The affinity of the compounds of formula (I) for the AMPA receptor wasdetermined by studying the antagonism of the specific binding of ³H!AMPA to membranes of rat cerebral cortex (HONORE et al., Neuroscienceletters, 54, 27 (1985)). ³ H!AMPA is incubated in the presence of 0.2 mgof proteins at 4° C. for 30 minutes in 10 mM KH₂ PO₄, 100 mM KSCNbuffer, pH 7.5. Non-specific binding is determined in the presence of 1mM L-glutamate. Bound radioactivity is separated by filtration onPharmacia filters (Printed Filtermate A). The inhibitory activity ofthese products is less than or equal to 100 μM.

The affinity of the compounds of formula (I) for the glycine site linkedto the NMDA receptor was determined by studying the antagonism of thespecific binding of ³ H!DCKA to membranes of rat cerebral cortexaccording to the method described by T. CANTON et al., J. Pharm.Pharmacol., 44, 812 (1992). ³ H!DCKA (20 nM) is incubated in thepresence of 0.1 mg of proteins at 4° C. for 30 minutes in 50 mM HEPESbuffer, pH 7.5. Non-specific binding is determined in the presence of 1mM glycine. Bound radioactivity is separated by filtration on WhatmanGF/B filters. The inhibitory activity of these products is less than orequal to 100 μM.

The compounds of formula (I) possess low toxicity. Their LD₅₀ is greaterthan 50 mg/kg via the IP route in mice.

Preferred compounds of formula (I) are those for which R represents aCH--R₆ radical in which R₆ represents a hydrogen atom or an --NR ₁₄ R₁₅radical, or R represents a C═R₇ radical in which R₇ represents a CH--R₁₉radical and R₁₉ represents an -alk-COOR₁₀ radical, or R represents aC(R4)R5 radical in which R₄ represents an alkyl radical and R₅represents an -alk-COOR₁₀ radical, R₁ represents a hydrogen or halogenatom or an --NH--CO--NR₁₁ R₁₂ radical and R₂ represents a hydrogen atom.

Preferably, the radical R₁ is at position 7 or 8.

Among these compounds, the preferred ones are the following:

1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione,

8-chloro-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione.

(5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno 1,2-b!pyrazin-5-yl)aceticacid,

5-amino-8-chloro-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione,

7-(3-phenylureido)-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione,

(E)-5-carboxymethylene-8-chloro-1,4-dihydroindeno1,2-b!pyrazine-2,3-dione,

(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetic acid,

(+)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno 1,2-b!pyrazin-5-yl)aceticacid,

(-)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno 1,2-b!pyrazin-5-yl)aceticacid,

(+)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetic acid,

(-)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl) acetic acid, and their salts.

The examples which follow illustrate the invention.

EXAMPLE 1

1.25 g of 2-ethoxalylamino-1-indanone are added rapidly to a solution of12.5 g of ammonium acetate in 50 ml of acetic acid brought to refluxunder nitrogen. After 18 hours of reflux, the reaction medium is cooledto a temperature in the region of 20° C. The precipitate formed isfiltered off, washed copiously with water and dried under a partialvacuum (1 mm Hg; 0.13 kPa) at 50° C. 0.77 g of 1,4-dihydro-5H-indeno1,2-b!pyrazine-2,3-dione are thereby obtained in the form of a greenpowder, the melting point of which is above 260° C. (analysis C₁₁ H₈ N₂O₂ ; 1.18 H₂ O; % calculated C: 66.00; H: 4.03; N: 13.99; % found C:65.7; H: 3.9; N: 13.9).

2-Ethoxalylamino-1-indanone may be prepared according to the followingprotocol: 6 g of 2-amino-1-indanone hydrochloride and 26.7 ml ofethoxalyl chloride are dissolved in 300 ml of tetrahydrofuran andstirred under nitrogen. 26.7 ml of triethylamine are added dropwise tothe reaction mixture, and the reaction is continued for 90 minutes at atemperature in the region of 20° C. The mixture is then filtered throughCelite and the filtrate concentrated to dryness under reduced pressure(15 mm Hg; 2 kPa). The residue is purified by flash chromatography on asilica column using a mixture of ethyl acetate and cyclohexane (20:80 byvolume) as eluant. 1.5 g of expected product are thereby obtained in theform of an orange-coloured solid melting at 135° C.

2-Amino-1-indanone hydrochloride may be obtained in the followingmanner: a solution of sodium ethylate, prepared from 15.2 g of sodiumand 770 ml of absolute ethanol, is added dropwise at 0° C. and undernitrogen to 200 g of 1-indanone oxime p-toluenesulphonate dissolved in3.7 litres of anhydrous toluene. The reaction is continued for 40 hoursat 0° C. The suspension is then filtered through Celite and the filtratewashed with water (400 ml). The toluene solution is treated with INhydrochloric acid (4×400 ml) and the aqueous phase concentrated todryness under reduced pressure (15 mm Hg; 2 kPa) at 40° C. The residueobtained is taken up in acetone, filtered off and dried to yield 29.8 gof expected product in the form of a brown solid which decomposes onheating.

1-Indanone oxime p-toluenesulphonate may be prepared in the followingway: 532 g of p-toluenesulphonyl chloride dissolved in 600 ml ofpyridine are added dropwise to 186.1 g of 1-indanone oxime dissolved in900 ml of pyridine at 0° C. and under nitrogen. After 3 hours ofreaction at 0° C., the reaction medium is poured into 3 litres ofice-cold water. The precipitate formed is filtered off, washed withwater and dried. 354 g of expected product are thereby obtained in theform of a white solid melting at 150° C.

1-Indanone oxime may be obtained in the following manner: 366 g ofhydroxylamine hydrochloride, 366 g of potassium carbonate and 340 ml ofdistilled water are added to 200 g of 1-indanone dissolved in 3.4 litresof methanol. The mixture is brought to reflux for 18 hours. Aftercooling, the suspension formed is filtered, and the residue is washedwith water and then with methanol and dried under reduced pressure (1 mmHg; 0.13 kPa) to yield 186.1 g of expected product in the form of awhite solid melting at 154° C.

EXAMPLE 2

35 g of ammonium acetate are solubilized in 70 ml of acetic acid. 12.2 gof 6-chloro-2-ethoxalylamino-1-indanone are added to this solution andthe mixture is brought to reflux for 6 hours. The reaction medium isthen concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa),and the oil obtained taken up with 100 ml of distilled water. Theprecipitate formed is filtered off, washed with water and dried under apartial vacuum (1 mm Hg; 0.13 kPa) at 40° C. 8.05 g of8-chloro-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione are obtained inthe form of a brown solid, the melting point of which is above 260° C.(NMR spectrum: 300 MHz; (CD₃)₂ SO-d₆ ; δ in ppm!: 3.56 (s, 2H: --CH₂-9); 7.15 (dd, J=8 and 2 Hz, 1H: --H7); 7.43 (dd, J=8 Hz, 1H: --H8);7.62 (d, J=2 Hz, 1H: --H5); from 11.75 to 12.75 (widely spread unres.comp.: --NHCO--)).

6--Chloro-2-ethoxalylamino-1-indanone may be obtained in the followingmanner: in a three-necked flask cooled to 0C, 8.4 g of2-amino-6-chloro-1-indanone hydrochloride are suspended in 100 ml oftetrahydrofuran, 5.53 ml of ethoxalyl chloride dissolved in 30 ml of thesame solvent are then added and lastly 12.7 ml of triethylaminedissolved in 70 ml of tetrahydrofuran are added dropwise so that thetemperature does not rise. The reaction is continued for 2 hours, duringwhich the temperature rises slowly to 20° C. The precipitate formed isfiltered off on Celite and the filtrate concentrated to dryness underreduced pressure. The residue obtained is taken up in 50 ml of ethylether, filtered off and dried under a partial vacuum (1 mm Hg; 0.13 kPa)at 40° C. 9.3 g of expected product are thereby obtained in the form ofa brown solid melting at 153° C.

2-Amino-6-chloro-1-indanone hydrochloride is prepared in the same way asin Example 1 for the preparation of 2-amino-1-indanone, starting from57.5 g of 6-chloro-1-indanone oxime p-toluenesulphonate, 3.94 g ofsodium, 200 ml of absolute ethanol and 1 litre of anhydrous toluene.After 15 hours of reaction at 0° C., the precipitate formed is filteredoff on Celite, the filtrate washed with water and then extracted with INhydrochloric acid (2×500 ml) and the aqueous phase concentrated todryness under reduced pressure. 10.5 g of expected product are obtainedin the form of a brown-green solid, the melting point of which is above260° C.

6--Chloro-1-indanone oxime p-toluenesulphonate may be prepared accordingto the protocol described in Example 1 for the preparation of 1-indanoneoxime p-toluenesulphonate, starting from 33 g of 6-chloro-1-indanoneoxime, 69.3 g of p-toluenesulphonyl chloride and 330 ml of pyridine.57.5 g of expected product are obtained in the form of a beige solidmelting at 170° C.

6--Chloro-1-indanone oxime may be prepared according to the protocoldescribed in Example 1 for the preparation of 1-indanone oxime, startingfrom 32.4 g of 6-chloro-1-indanone, 47.3 g of hydroxylaminehydrochloride, 47 g of potassium carbonate, 53 ml of distilled water and530 ml of methanol. 33 g of expected product are obtained in the form ofa yellow solid melting at 167° C.

6--Chloro-1-indanone may be prepared according to the process describedby R. Sieka and W. Kellermann, Chem. Ber., 75, 1730 (1942).

EXAMPLE 3

A mixture of 0.7 g of ethyl (5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate, 40 ml of dioxane and 9 ml of 8N hydrochloricacid is heated to 40° C. for 90 hours. The reaction mixture is thenevaporated in a rotary evaporator, and the evaporation residue istriturated in 20 ml of water, filtered off and rinsed with distilledwater (2×10 ml) and then with isopropyl ether (10 ml). After drying at60° C. under vacuum (1 mm Hg; 0.13 kPa), 0.4 g of(5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno 1,2-b!pyrazin-5-yl)acetic acidis obtained in the form of a pale yellow solid melting above 260° C.(Analysis % calculated C: 61.76; H: 4.44; N: 10.29; 0: 23.51; % found C:61.8; H: 4.6; N: 10.4).

Ethyl (5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate may be prepared in the following way: amixture of 2.1 g of ethylN-(1-ethoxycarbonylmethyl-1-methyl-3-oxo-2-indanyl)oxamate, 20 ml ofacetic acid and 4.6 g of ammonium acetate is heated to reflux for 4hours. The reaction mixture is then concentrated in a rotary evaporator,50 ml of water are added and the mixture is subjected to two extractionswith ethyl acetate (2×50 ml). The organic extract is dried overmagnesium sulphate, filtered and evaporated in a rotary evaporator. Theyellow oil obtained (2 g) is purified by crystallization in 15 ml ofacetonitrile. After filtration and washing of the crystals with 2×10 mlof acetonitrile and 2×10 ml of isopropyl ether, 0.7 g of ethyl(5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno 1,2-b!pyrazin-5-yl) acetate isobtained in the form of a pale yellow solid (¹ H NMR spectrum 300 MHz,(CD₃)₂ SO-d₆, δ in ppm!: 0.77 (t, J=7 Hz, 3H: ethyl CH₃); 1.40 (s, 3H:CH₃); 3.00 (limiting AB, 2H: CH₂); 3.20 (q, J=7 Hz, 2H: ethyl COOCH₂);7.12 and 7.25 (2 t, J=8 Hz, 2H: H 6 and H 7); 7.43 and 7.50 (2 d, J=8Hz, 2H: H 5 and H 8)).

Ethyl N-(1-ethoxycarbonylmethyl-1-methyl-3-oxo-2-indanyl)oxamate may beprepared in the following manner: a mixture of 5.5 g of ethyl(2-amino-1-methyl-3-oxo-1-indanyl)acetate hydrochloride and 100 ml ofdichloromethane is cooled to a temperature in the region of 20° C., 2.6ml of ethoxalyl chloride are added, and a solution of 6.1 ml oftriethylamine in 20 ml of dichloromethane is then added slowly while thetemperature of the reaction medium is maintained close to 0° C. When theaddition is complete, the temperature of the reaction mixture is allowedto rise to about 20° C. The mixture is then filtered and the filtrate iswashed with distilled water (2×80 ml). The organic solution is driedover magnesium sulphate, filtered and evaporated in a rotary evaporatorto give 6.2 g of ethylN-(1-ethoxycarbonylmethyl)-1-methyl-3-oxo-2-inddanyl) oxamate in theform of a brown oil (¹ H NMR spectrum 200 MHz, (CD₃)₂ SO-d₆, δ in ppm!.A 50:50 mixture of isomers is observed: 0.88-1.03 and 1.34 (3 t, J=7 Hz,respectively 1.5H, 1.5H and 3H: ethyl CH₃); 1.21 and 1.65 (2 s, 1.5Heach: CH₃); 2.75 and 3.03 (2 AB, respectively J=15 Hz and J=16 Hz, 2H intotal: CH₂); 3.78, 3.92 and 4.32 (3 mts, 4H in total: ethyl COOCH₂);4.81 and 5.10 (2 d, J=9 Hz, 1H in total: CH); from 7.40 to 7.85 (mt, 4H,aromatic H); 8.47 and 9.29 (2 d broad, J=9 Hz, 1H in total: NHCO)).

Ethyl (2-amino-1-methyl-3-oxo-1-indanyl)-acetate hydrochloride may beprepared in the following way: a solution of 7.32 g of ethyl(2-hydroxyimino-1-methyl-3-oxo-1-indanyl)acetate hydrochloride in 150 mlof acetic acid is saturated with gaseous hydrochloric acid, and themixture is then hydrogenated for 20 hours at a pressure of 1.8 bar ofhydrogen at a temperature in the region of 20° C. in the presence of 1.4g of palladium on charcoal (palladium content 10%). The reaction mixtureis filtered and concentrated in a rotary evaporator. The evaporationresidue is treated with 50 ml of ethyl acetate, and 100 ml of ethylether are added slowly to the brown solution obtained. The whiteprecipitate which appears is filtered off, washed with ethyl ether (2×50ml) and dried. 5.5 g of ethyl (2-amino-1-methyl-3-oxo-1-indanyl)acetatehydrochloride are obtained in the form of an off-white solid melting atabout 172° C. with decomposition (¹ H NMR spectrum 300 MHz, (CD₃)₂SO-d₆, δ in ppm!. A 60:40 mixture of isomers is observed: 0.86-1.06 (2t, J=7 Hz, 3H in total: ethyl CH₃); 1.36 and 1.75 (2 s, 3H in total:CH₃); 2.92, 3.20 and 3.46 (respectively limiting AB and 2 d (J=16 Hz),2H in total: CH₂); 3.80 and 3.96 (2 mts, 2H in total: ethyl COOCH₂);4.22 and 4.50 (2 s, 1H in total: CH); from 7.40 to 7.90 (mt, 4H:aromatic H); 8.94 (unres. comp., 3H in total: NH₃ ⁺ Cl⁻)).

Ethyl (2-hydroxyimino-1-methyl-3-oxo-1-indanyl)acetate hydrochloride maybe prepared according to the process described in U.S. Pat. No.3,703,529.

EXAMPLE 4

0.39 g of 5-acetamido-8-chloro-1,4-dihydro-5H-indeno1,2-b!pyrazine-2,3-dione suspended in 5 ml of 6N hydrochloric acid isbrought to reflux for 5 hours. After cooling to a temperature in theregion of 20° C., the insoluble matter is filtered off, washed withwater and then with methanol and taken up in 10 ml of a mixture of hotwater and methanol (50:50 by volume). After a few minutes of stirring,the insoluble matter is filtered off and dried under a partial vacuum (1mm Hg; 0.13 kPa) to yield 0.1 g of5-amino-8-chloro-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dionehydrochloride in the form of a grey solid, the melting point of which isabove 260° C. (¹ H NMR spectrum 250 MHz, (CD₃)₂ SO-d₆, δ in ppm): 5.15(s, 1H: CH 9); 7.39 (dd, J=8 and 2 Hz, 1H: H 7); 7.71 (d, J=2 Hz, 1H: H5); 7.75 (d, J=8 Hz), 1H: H 8); from 8.70 to 9.20 (spread unres. comp.,3H: NH₃ ⁺ Cl⁻); from 12.00 to 12.70 (spread unres. comp., 2H: NHCOCONH).

5-Acetamido-8-chloro-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione maybe prepared according to the following procedure: 1 g of zinc powder isadded in small portions to 1.74 g of5-hydroxyimino-8-chloro-1,4-dihydroindeno 1,2-b!-pyrazine-2,3-dionesuspended in 35 ml of acetic acid. The reaction medium is then broughtto 90° C. for 1 hour. After cooling to a temperature in the region of20° C., 0.7 ml of acetic anhydride is added and stirring is continued atthe same temperature for 48 hours. 50 ml of distilled water are thenadded to the reaction medium, and the insoluble matter is filtered off,washed with acetone and with methanol to yield 0.9 g of expected productin the form of a brown solid, the melting point of which is above 260°C. (¹ H NMR spectrum 300 MHz, (CD₃)₂ SO-d₆, δ in ppm): 1.94 (s, 3H:COCH₃) 5.70 (d, J=8 Hz, 1H: CH 9); 7.20 (dd, J=8 and 2 Hz, 1H: H 7);7.33 (d, J=8 Hz, 1H: H 8); 7.60 (d, J=2 Hz, 1H: H 5); 8.40 (d, J=8 Hz,1H: NHCO); 12.15 and 12.35 (2 unres. comp., 1H each: NHCOCONH).

5-Hydroxyimino-8-chloro-1,4-dihydroindeno 1,2-b!pyrazine-2,3-dione maybe prepared in the following way: 1.07 g of 60% sodium hydride are addedin small portions to 2.75 g of 8-chloro-1,4-dihydro-5H-indeno1,2-b!pyrazine-2,3-dione dissolved in 45 ml of dimethyl sulphoxide. Assoon as the gaseous evolution has ceased, 1.39 ml of isoamyl nitritedissolved in 35 ml of dimethyl sulphoxide are added to the reactionmedium over approximately 15 minutes. The reaction is continued for 1.5hours at a temperature in the region of 20° C. The reaction medium isthen poured onto 500 ml of ice and thereafter diluted with 100 ml ofmethanol. The precipitate is filtered off and washed with methanol toyield 2.44 g of expected product in the form of a black solid, which isused without further purification in the subsequent syntheses. (¹ H NMRspectrum 200 MHz, (CD₃)₂ SO-d₆ with addition of a few drops of CD₃COOD-d₄, δ in ppm!. The mixture is observed of the two isomers, syn andanti, in the proportions 65:35: 7.23 (dd, J=8 and 2 Hz, 1H: H 7); 7.51and 8.01 (2 d, J=8 Hz, 1H in total: H 8); 7.56 and 7.63 (2 d, J=2 Hz, 1Hin total: H 5).

EXAMPLE 5

1.92 ml of phenyl isocyanate are added at a temperature in the region of20° C. to a solution of 1.5 g of 7-amino-1,4-dihydro-5H-indeno1,2-b!pyrazine-2,3-dione hydrochloride and 2.48 ml of triethylamine in20 ml of dimethylformamide. After overnight stirring at the sametemperature, the precipitate formed is filtered off, washed with waterand dried under a partial vacuum (1 mm Hg; 0.13 kPa) at 40° C. to yield1.4 g of 7-(3-phenylureido)-1,4-dihydro-5H-indeno1,2-b!pyrazine-2,3-dione in the form of a greenish solid, the meltingpoint of which is above 260° C. (Analysis C₁₈ H₁₄ N₄ O₃ ; 4.0 H₂ O; %calculated C: 64.66; H: 4.22; N: 16.76; % found C: 64.4; H: 4.5; N:16.8; ¹ H NMR spectrum 250 MHz, (CD₃)₂ SO-d₆, δ in ppm!: 3.58 (s, 2H CH₂9); 7.00 (t, J=7.5 Hz, 1H: aromatic H of the phenyl at para with respectto the ureido); 7.30 (t, J=7.5 Hz, 2H: aromatic H of the phenyl at metawith respect to the ureido); 7.50 (d, J=7.5 Hz, 2H: aromatic H of thephenyl at ortho with respect to the ureido); from 7.20 to 7.60 (mt, 2H:H 5 and H 6); 7.72 (s broad, 1H: H 8); 8.80 (s broad, 2H: ArNHCONH);12.00 and 12.28 (2 unres. comp. 1H each: NHCOCONH).

7-Amino-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione hydrochloride maybe obtained in the following manner: 100 ml of concentrated hydrochloricacid are added dropwise to 6 g of 7-nitro-1,4-dihydro-5H-indeno1,2-b!pyrazine-2,3-dione suspended in 135 ml of methanol, followed by4.27 g of iron powder and 27 ml of dimethylformamide. The reactionmixture is stirred for 1 hour at room temperature and then treated againwith 4.27 g of iron powder and 27 ml of dimethylformamide. The reactionis continued for 2 hours at 80° C. and, after cooling to a temperaturein the region of 20° C., the insoluble matter is filtered off, washedwith methanol and dried to yield 5.1 g of expected product in the formof an ochre powder, the melting point of which is above 260° C.(¹ H NMRspectrum 250 MHz, (CD₃)₂ SO-d₆ plus a few drops of CD₃ COOD-d₄, δ inppm!: 3.60 (s, 2H: CH₂ 9); 7.34 (d broad, J=8 Hz, 1H: H 6); 7.47 (sbroad, 1H: R 8); 7.66 (d, J=8 Hz, 1H: H 5).

7-Nitro-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione may be preparedaccording to the following procedure: 5.35 g of potassium nitrate areadded to a solution, cooled to -5° C., of 10 g of 1,4-dihydro-5H-indeno1,2-b!pyrazine-2,3-dione in 170 ml of sulphuric acid in such a way thatthe temperature does not exceed 0° C. The reaction is continued for 3hours at a temperature in the region of 20° C. The reaction medium isthen added to ice, and the precipitate formed filtered off, washed withwater and dried to yield 6 g of expected nitrated product in the form ofan orange-coloured powder, the melting point of which is above 260° C.(¹ H NMR spectrum 300 MHz, (CD₃)₂ SO-d₆, δ in ppm!: 3.73 (s, 2H CH₂ 9);7.71 (d, J=8 Hz, 1H: H 5); 8.27 (dd, J=8 and 2.5 Hz, 1H: H 6); 8.33 (sbroad, 1H: H 8); from 12.10 to 12.70 (unres. comp. 2H: NHCOCONH).

EXAMPLE 6

0.94 g of sodium hydride is added gradually to 1 g ofB-chloro-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione and 0.59 g ofglyoxylic acid hydrate dissolved in 15 ml of dimethyl sulphoxide whilethe reaction medium is maintained at a temperature in the region of 20°C. After 18 hours of reaction at the same temperature, 5 ml of aceticacid are added to the reaction medium and the mixture is brought toreflux for 4 hours. After cooling, the mixture is filtered, and theblack insoluble matter washed with water and with methanol, then takenup in 15 ml of methanol and stirred overnight at room temperature. Theinsoluble matter is filtered off, washed with acetone and dried under apartial vacuum (1 mm Hg; 0.13 kPa) at 35° C. 0.7 g of(E)-5-carboxymethylene-8-chloro-1,4-dihydroindeno1,2-b!pyrazine-2,3-dione is thereby obtained in the form of a dark brownsolid, the melting point of which is above 260° C. (¹ H NMR spectrum 200MHz, (CD₃)₂ SO-d₆, δ in ppm!: 6.69 (s broad, 1H: ═CH); 7.15 (d broad,J=8.5 Hz, 1H: H 7); 7.54 (s broad, 1H: H 5); 7.67 (d, J=8.5 Hz), 1H: H8); from 11.5 to 13.00 (spread unres. comp., 2H: OH); 15.90 (unres.comp. 1H: COOH).

EXAMPLE 7

A mixture of 2.27 g of ethyl(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate, 120 ml of dioxane and 25 ml of 8N aqueoushydrochloric acid solution is heated to a temperature in the region of80° C. for 4 hours. The reaction mixture is then evaporated underreduced pressure, and the evaporation residue is triturated in 35 ml ofan ethanol/water (85:15 by volume) mixture, filtered and washed withdistilled water (2 times 10 ml). The product obtained is taken up in 68ml of 0.1N aqueous sodium hydroxide solution. The insoluble matter isseparated by filtration, and the filtrate is neutralized by adding 6.8ml of 1N aqueous hydrochloric acid solution. The solid obtained isseparated by filtration, washed with distilled water (2 times 5 ml) anddried in the air. 0.41 g of(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno 1,2-b!pyrazin-5-yl)acetic acid is thereby obtained in the form of an ochre-coloured solidmelting above 300° C. (¹ H NMR spectrum 200 MHz, (CD₃)₂ SO-d₆, δ inppm!: 1.39 (3H, s, CH₃); 2.93 (2H, m, --CH₂ --CO); 7.19 (lH, dd, J=8 and2 Hz, arom H); 7.48 (1H, d, J=8 Hz, arom H); 7.56 (1H, d, 2=2 Hz, aromH); 12.18 (1H, s, --NH--); 12.24, s, --NH); Analysis, % calculated C:54.83; H: 3.61; Cl: 11.56; N: 9.13; 0: 20.87; % found C: 55.2; H: 3.4;Cl: 11.2; N: 9.0; O: 18.6).

Ethyl (8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate may be prepared in the same way as isdescribed in Example 3 for the preparation of ethyl(5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno 1,2-b!pyrazin-5-yl)acetate,but starting from 21.5 g of ethylN-(5-chloro-1-ethoxycarbonylmethyl-1-methyl-3-oxo-2-indanyl)oxamate and43.6 g of ammonium acetate in 400 ml of acetic acid. The brown oilobtained (32 g) is triturated in 50 ml of diethyl ether. After filteringoff the solid obtained and washing with 2 times 10 ml of diethyl ether,10 g of ethyl (8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate are thereby obtained in the form of a yellowsolid, which is used in the subsequent syntheses without furtherpurification.

EthylN-(5-chloro-1-ethoxycarbonylmethyl-1-methyl-3-oxo-2-indanyl)oxamate maybe prepared in the same way as is described in Example 3 for thepreparation of ethylN-(1-ethoxycarbonylmethyl-1-methyl-3-oxo-2-indanyl)oxamate, but startingfrom 18 g of ethyl (2-amino-5-chloro-1-methyl-3-oxo-1-indanyl)acetatehydrochloride, 7.6 ml of ethoxalyl chloride and 17.5 ml of triethylaminein 200 ml of dichloromethane. 20 g of ethylN-(5-chloro-1-ethoxycarbonylmethyl-1-methyl-3-oxo-2-indanyl)oxamate arethereby obtained in the form of a brown oil, which is used in thesubsequent syntheses without further purification.

Ethyl (2-amino-5-chloro-1-methyl-3-oxo-1-indanyl)acetate hydrochloridemay be prepared in the same way as is described in Example 3 for thepreparation of ethyl (2-amino-1-methyl-3-oxo-1-indanyl)acetatehydrochloride, but starting from 20 g of ethyl(5-chloro-2-hydroxyimino-1-methyl-3-oxo-1-indanyl)acetate hydrochloridein 450 ml of acetic acid saturated with gaseous hydrochloric acid and inthe presence of 4 g of palladium on charcoal (palladium content 10%).After churning in 200 ml of diethyl ether, 18.4 g of ethyl(2-amino-5-chloro-1-methyl-3-oxo-1-indanyl)acetate hydrochloride arethereby obtained in the form of a pale green-white solid melting at 134°C.

Ethyl (5-chloro-2-hydroxyimino-1-methyl-3-oxo-1-indanyl)acetatehydrochloride may be prepared in the following way: 26.7 ml oftert-butyl nitrite are added to a solution of 40 g of ethyl(5-chloro-1-methyl-3-oxo-1-indanyl)acetate in 150 ml of ethyl ether and55 ml of a 5.5N ethereal hydrogen chloride solution cooled to atemperature in the region of 10° C. The reaction mixture is stirred for2 hours at a temperature in the region of 25° C. and then concentratedto dryness under reduced pressure. The oily residue obtained is taken upin 30 ml of ethyl acetate and evaporated to dryness under reducedpressure. The latter operation is carried out 5 times in order to removethe excess tert-butyl nitrite by azeotropic distillation. 43.7 g ofethyl (5-chloro-2-hydroxyimino-1-methyl-3-oxo-1-indanyl)acetatehydrochloride are thereby obtained in the form of a pale yellow solidmelting at 144° C.

Ethyl (5-chloro-1-methyl-3-oxo-1-indanyl)acetate may be prepared in thefollowing way: 15 ml of oxalyl dichloride are added slowly to a mixtureof 40 g of (5-chloro-1-methyl-3-oxo-1-indanyl)acetic acid and 0.5 ml ofN,N-dimethylformamide in 400 ml of dichloromethane. After 3 hours at atemperature in the region of 25° C., 60 ml of ethanol are added slowly.The reaction mixture is left stirring for 12 hours and is then washedwith 2 times 50 ml of saturated aqueous sodium hydrogen carbonatesolution, 50 ml of distilled water and 100 ml of saturated aqueoussodium chloride solution, dried over magnesium sulphate and concentratedto dryness under reduced pressure. 41 g of ethyl(5-chloro-1-methyl-3-oxo-1-indanyl)acetate are thereby obtained in theform of a brown oil, which is used in subsequent syntheses withoutfurther purification.

(5-Chloro-1-methyl-3-oxo-1-indanyl)acetic acid may be prepared in thefollowing way: a mixture of 74 g of 3-(4-chlorophenyl)-3-methylglutaricacid in 300 ml of concentrated sulphuric acid is heated to reflux for 24hours. After returning to a temperature in the region of 25° C., thereaction medium is poured slowly into 1 litre of ice-cold water and isthen extracted with 3 times 500 ml of ethyl acetate. The combinedorganic phases are washed with 3 times 500 ml of water and 500 ml ofsaturated aqueous sodium chloride solution, dried over magnesiumsulphate and concentrated to dryness under reduced pressure. The crudeoil (60 g) is triturated in 50 ml of ethyl ether. The solid obtained isseparated by filtration, washed with 20 ml of ethyl ether and dried inthe air. 48 g of (5-chloro-1-methyl-3-oxo-1-indanyl)acetic acid arethereby obtained in the form of a cream-coloured solid melting at 119°C.

3-(4-Chlorophenyl)-3-methylglutaric acid may be prepared in thefollowing way: a solution of 110 g of2,4-dicyano-3-methyl-3-(4-chlorophenyl)glutarimide in a mixtureconsisting of 470 ml of water, 470 ml of concentrated sulphuric acid and300 ml of acetic acid is heated to reflux for 42 hours. After returningto a temperature in the region of 25° C., the reaction medium is pouredinto 2 litres of ice-cold water. The precipitate formed is separated byfiltration, washed with 2 times 50 ml of distilled water and dried inthe air. 76.3 g of 3-(4-chlorophenyl)-3-methylpentanedioic acid arethereby obtained in the form of a cream-coloured solid melting at 128°C.

2,4-Dicyano-3-methyl-3-(4-chlorophenyl)glutarimide may be prepared inthe following way: 37 g of cyanoacetamide are added slowly at atemperature in the region of 5° C. to an ethanolic solution of sodiumethylate obtained by adding 10.2 g of sodium to 400 ml of ethanol. After15 minutes, a solution of 110 g of ethyl2-cyano-3-(4-chlorophenyl)-2-butenoate is added to the suspensionobtained. The reaction mixture is stirred for 4 hours at a temperaturein the region of 25° C. and is then poured into 500 ml of distilledwater. The reaction medium is cooled to a temperature in the region of5° C. and then acidified by adding 85 ml of concentrated aqueoushydrochloric acid solution. The precipitate is separated by filtration,washed with 2 times 50 ml of water and dried in the air. 112 g of2,4-dicyano-3-methyl-3-(4-chlorophenyl)glutarimide are thereby obtainedin the form of a yellow solid melting at 258° C.

Ethyl 2-cyano-3-(4-chlorophenyl)-2-butenoate may be prepared in thefollowing way: a mixture of 130 ml of 4-chloroacetophenone, 107 ml ofethyl cyanoacetate, 15.4 g of ammonium acetate and 48 ml of acetic acidin 200 ml of toluene is heated to reflux for 12 hours, removing thewater formed during the reaction by azeotropic distillation. Afterreturning to a temperature in the region of 25° C., the reaction mixtureis diluted with 100 ml of toluene, washed with 2 times 100 ml ofdistilled water and with 100 ml of saturated aqueous sodium chloridesolution, dried over magnesium sulphate and concentrated to drynessunder reduced pressure. The crude oil obtained is distilled underreduced pressure (pressure in the region of 30 mm of Hg) and thefraction distilling between 140 and 180° C. is collected. 110 g of ethyl2-cyano-3-(4-chlorophenyl)-2-butenoate are thereby obtained in the formof a thick yellow oil, which is used in the subsequent syntheses withoutfurther purification.

EXAMPLE 8

The procedure is as in Example 3 but starting from 1.2 g of ethyl(+)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno1,2-b!pyrazin-5-yl)acetate, 70 ml of dioxane and 15 ml of 8Nhydrochloric acid. The acid obtained (0.64 g) is purified bysolubilization in 40 ml of distilled water and 0.2 g of sodium hydrogencarbonate, washing of this solution with 15 ml of ethyl acetate andacidification of the aqueous phase with 2.5 ml of 1N hydrochloric acid.After the addition of 12 g of sodium chloride, the precipitate formed isfiltered off, washed with 5 ml of distilled water and then 10 ml ofisopropyl ethyl and dried at 60° C. under vacuum (1 mmHg; 0.13 kPa). Theacid thus purified (0.27 g) is converted to the sodium salt bydissolution in 10 ml of 0.1N sodium hydroxide, filtration andlyophilization. 0.28 g of (+)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno1,2-b!pyrazin-5-yl)acetic acid is obtained in the form of the sodiumsalt, melting above 260° C. (Analysis, % calculated C: 57.15; H: 3.77;N: 9.52; Na: 7.81; O: 21.75; % found C: 57.1; N: 9.0; α_(D) ²⁰ =+24.1(water; c=0.5%)).

Using the procedure described above, but starting from 1.2 g of ethyl(-)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno1,2-b!pyrazin-5-yl)acetate, 70 ml of dioxane and 15 ml of 8Nhydrochloric acid, 0.27 g of(-)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno 1,2-b!pyrazin-5-yl)aceticacid is obtained in the form of the sodium salt, melting above 260° C.(Analysis, % calculated C: 57.15; H: 3.77; N: 9.52; Na: 7.81; O: 21.75;% found C: 57.2; H: 3.8; N: 9.1; α_(D) ²⁰ =-23.6 (water; c=0.5%)).

Ethyl (+)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno1,2-b!pyrazin-5-yl)acetate and ethyl(-)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno 1,2-b!pyrazin-5-yl)acetateare prepared by chromatography of the racemic product on a CHIRACEL ODDAICEL chiral column (250 mm in length and 60 mm in diameter) using aseluent an ethanol/heptane (70:30 by volume) mixture at a flow rate of 80ml/minute. Starting from 3×1.1 g of ethyl(+/-)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno1,2-b!pyrazin-5-yl)acetate, 1.57 g of ethyl(+)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno 1,2-b!pyrazin-5-yl)acetateare obtained in the form of a yellow solid (α_(D) ²⁰ =+51.2 (methanol;c=0.5%)) and 1.52 g of ethyl(-)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno 1,2-b!pyrazin-5-yl)acetateare obtained in the form of a yellow solid (α_(D) ²⁰ =+24.1 (water;c=0.5%)).

EXAMPLE 9

Using the procedure described in Example 8, but starting from ethyl(+)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate,(+)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetic acid is obtained, and starting from ethyl(-)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate,(-)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetic acid is obtained.

Ethyl (+)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate and ethyl(-)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate are prepared as described in Example 8,starting from the mixture ethyl(+/-)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetate.

The medicinal products according to the invention consist of a compoundof formula (I) or a salt of such a compound, in the pure state or in theform of a composition in which it is combined with any otherpharmaceutically compatible product, which may be inert orphysiologically active. The medicinal products according to theinvention may be employed orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders(gelatin capsules, wafer capsules) or granules may be used. In thesecompositions, the active principle according to the invention is mixedwith one or more inert diluents such as starch, cellulose, sucrose,lactose or silica, under a stream of argon. These compositions can alsocomprise substances other than diluents, for example one or morelubricants such as magnesium stearate or talc, a colouring, a coating(dragees) or a varnish.

As liquid compositions for oral administration, pharmaceuticallyacceptable solutions, suspensions, emulsions, syrups and elixirs may beused, containing inert diluents such as water, ethanol, glycerol,vegetable oils or liquid paraffin. These compositions can also comprisesubstances other than diluents, for example wetting, sweetening,thickening, flavouring or stabilizing products.

The sterile compositions for parenteral administration can preferably besolutions, aqueous or non-aqueous, suspensions or emulsions. As asolvent or vehicle, it is possible to employ water, propylene glycol, apolyethylene glycol, vegetable oils, especially olive oil, injectableorganic esters, for example ethyl oleate, or other suitable organicsolvents. These compositions can also contain adjuvants, especiallywetting, tonicity, emulsifying, dispersing and stabilizing agents. Thesterilization may be carried out in several ways, for example by asepticfiltration, by incorporating sterilizing agents in the composition, byirradiation or by heating. They may also be prepared in the form ofsterile solid compositions which can be dissolved at the time of use insterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain, besides the active product, excipients such ascocoa butter, semi-synthetic glycerides or polyethylene glycols.

In human therapy, the compounds according to the invention areespecially useful for the treatment and/or prevention of conditionswhich require the administration of an AMPA receptor antagonist or anNMDA receptor antagonist. These compounds are, in particular, useful fortreating or preventing all ischaemias and especially cerebral ischaemia,the effects due to anoxia, the progression of neurodegenerativediseases, Huntington's chorea, Alzheimer's disease, amyotrophic lateralsclerosis, olivopontocerebellar atrophy and Parkinson's disease forepileptogenic and/or convulsive manifestations, for the treatment ofcerebral and spinal trauma, trauma associated with degeneration of theinner ear or the retina, anxiety, depression, schizophrenia, Tourette'ssyndrome and hepatic encephalopathy, as analgesics, anti-inflammatories,antianorectics, antimigraine drugs and antiemetics, and for treatingpoisoning by neurotoxins or other substances which are NMDA receptoragonists, as well as the neurological disorders associated with viraldiseases such as AIDS, rabies, measles and tetanus. These compounds arealso useful for prevention of the symptoms of drug and alcoholabstinence and of the inhibition of opiate addiction and dependence, aswell as for the treatment of defects associated with mitochondrialabnormalities such as mitochondrial myopathy, Leber's syndrome,Wernicke's encephalopathy, Rett's syndrome, homocysteinaemia,hyperprolinaemia, hydroxybutiric/aminoaciduria, saturnine encephalopathy(chronic lead poisoning) and sulphite oxidase deficiency.

Doses depend on the effect sought, the duration of the treatment and theadministration route used; they are generally between 10 mg and 100 mgdaily via the oral route for an adult, with single doses ranging from 5mg to 50 mg of active substance.

Generally speaking, the doctor will determine the appropriate dosage inaccordance with the age and weight and all other factors specific to thesubject to be treated.

The examples which follow illustrate some compositions according to theinvention:

EXAMPLE A

Hard gelatin capsules containing a 50 mg dose of active product andhaving the following composition are prepared according to the usualtechnique:

Compound of formula (I) . . . 50 mg

Cellulose . . . 18 mg

Lactose . . . 55 mg

Colloidal silica . . . 1 mg

Sodium carboxymethylstarch . . . 10 mg

Talc . . . 10 mg

Magnesium stearate . . . 1 mg

EXAMPLE B

Tablets containing a 50 mg dose of active product and having thefollowing composition are prepared according to the usual technique:

Compound of formula (I) . . . 50 mg

Lactose . . . 104 mg

Cellulose . . . 40 mg

Povidone . . . 10 mg

Sodium carboxymethylstarch . . . 22 mg

Talc . . . 10 mg

Magnesium stearate . . . 2 mg

Colloidal silica . . . 2 mg

Mixture of hydroxymethylcellulose, glycerol and titanium oxide(72:3.5:24.5) q.s. 1 finished film-coated tablet weighing 245 mg

EXAMPLE C

An injectable solution containing 10 mg of active product and having thefollowing composition is prepared:

Compound of formula (i) . . . 10 mg

Benzoic acid . . . 80 mg

Benzyl alcohol . . . 0.06 ml

Sodium benzoate . . . 80 mg

Ethanol, 95% . . . 0.4 ml

Sodium hydroxide . . . 24 mg

Propylene glycol . . . 1.6 ml

Water . . . q.s. 4 ml

We claim:
 1. A compound of formula (I): ##STR9## in which: --Rrepresents a CR₄ R₅, CHR₆, or C═R₇ radical,--R₁ and R₂, which may beidentical or different, represent: (1) hydrogen, (2) halogen, (3) alkyl,(4) alkoxy, (5) amino, (6) --N═CH--N(alk)alk', (7) nitro, (8) cyano, (9)phenyl, (10) imidazolyl, (11) SO₃ H, (12) hydroxyl, (13)polyfluoroalkoxy, (14) carboxyl, (15) alkoxycarbonyl, (16)--NH--CO--NR₁₁ R₁₂, (17) --N(alk)--CO--NR₁₁ R₁₂, (18)--N(alk--Ar)--CO--NR₁₁ R₁₂, (19) --NH--CS--NR₁₁ R₁₂, (20)--N(alk)--CS--NR₁₁ R₁₂, (21) --NH--CO--R₁₁, (22) --NH--CS--R₂₄, (23)--NH--C(═NR₂₇)--NR₁₀ R₁₂, (24) --N(alk)--C(═NR₂₇)--NR₁₀ R₁₂, (25)--CO--NR₁₀ R₁₂, (26) --NH--SO₂ --NR₁₀ R₁₂, (27) --N(alk)--SO₂ --NR₁₀R₁₂, (28) --NH--SO₂ --CF₃, (29) --NH--SO₂ -alk, (30) --NR₁₀ R₁₃, (31)--S(O)_(m) -alk-Ar, (32) --SO₂ --NR₁₀ R₁₂, (33) a 2-oxo-1-imidazolidinylradical in which position 3 is substituted or unsubstitited with analkyl radical, or (34) a 2-oxo-1-perhydropyrimidinyl radical in whichposition 3 is optionally substituted with an alkyl radical, --R₃represents an oxygen atom, --R₄ represents an alkyl radical, --R₅represents an -alk-COOR₁₀ radical, --R₆ represents a hydrogen atom or anNR₁₄ R₁₅ radical, --R₇ represents a C(COOR₁₀)R₂₀ radical in which R₂₀ isa hydrogen atom, --R₁₀ represents a hydrogen atom or an alkyl radical,--R₁₁ represents: (1) hydrogen, (2) alkyl having from 1 to 9 carbonatoms in an unbranched or branched chain, (3) alkoxy, (4) -alk-COOR₁₀,(5) -alk-Het, (6) -alk-NR₁₂ R₁₀, (7) phenylalkyl in which the phenylring is optionally substituted with one or more substituents selectedfrom (a) halogen atoms, (b) alkyl, (c) alkoxy, (d) nitro, (e) amino, (f)hydroxyl, (g) -alk-NH₂, (h) carboxyl, (i) alkoxycarbonyl, (j) cyano and(k) -alk-COOR₁₀, or (8) a phenyl radical optionally substituted with oneor more substituents selected from (a) halogen, (b) alkyl, (c) alkoxy,(d) nitro, (e) amino, (f) hydroxyl, (g) -alk-NH₂, (h) carboxyl, (i)alkoxycarbonyl, (j) cyano, (k) -alk-COOR₁₀, and (l) a -Het radical,--R₁₂ represents a hydrogen atom or an alkyl radical, --R₁₃ representsan alkyl, Het or alkoxycarbonyl radical, --R₁₄ and R₁₅ each represent ahydrogen atom, --R₂₄ represents an alkyl radical, --R₂₇ represents ahydrogen atom or an alkyl radical, -alk represents an alkyl radical,-alk' represents an alkyl radical, --Ar represents a phenyl radical, --mis equal to 0, 1 or 2 -Het represents a saturated or unsaturated, mono-or polycyclic heterocycle containing 1 to 9 carbon atoms and one or morehetero atoms, said one or more hetero atoms being O, S, or N, optionallysubstituted with one or more alkyl, phenyl or phenylalkyl radicals, itbeing understood that the alkyl and alkoxy radicals contain 1 to 6carbon atoms and are unbranched- or branched-chain radicals, the acylradicals contain 2 to 4 carbon atoms, wherein acyl represents a --CO-alkradical in which the alkyl has 2 to 4 carbon atoms, it also beingunderstood that the compound of formula (I) includes the E or Z isomerof a compound of formula (I) in which R represents a C═R₇ radical inwhich R₇ is a --C(COOR₁₀)R₂₀ radical in which R₂₀ is a hydrogen atom; anenantiomer or diastereoisomer of a compound of formula (I) in which Rrepresents a CR₄ R₅ or CHR₆ radical; or a salt of a compound of formula(I).
 2. The compound of formula (I) according to claim 1, wherein R₁represents hydrogen, a halogen atom, or an NH--CO--NR₁₁ R₁₂ radical andR₂ represents a hydrogen atom.
 3. A compound selectedfrom:1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione,8-chloro-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione,(5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno 1,2-b!pyrazin-5-yl)aceticacid, 5-amino-8-chloro-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione,7-(3-phenylureido)-1,4-dihydro-5H-indeno 1,2-b!pyrazine-2,3-dione,(E)-5-carboxymethylene-8-chloro-1,4-dihydroindeno1,2-b!pyrazine-2,3-dione,(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetic acid,(+)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno 1,2-b!pyrazin-5-yl)aceticacid, (-)-(5-methyl-2,3-dioxo-1,4-dihydro-1H-indeno1,2-b!pyrazin-5-yl)acetic acid,(+)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetic acid,(-)-(8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno1,2-b!pyrazin-5-yl)acetic acid, and the salts of said compounds.
 4. Acompound of formula (I) according to claim 1, wherein said R₁substituent is at position 7 or
 8. 5. A pharmaceutical composition forantagonizing an AMPA receptor which comprises a pharmaceuticallyeffective amount of at least one compound of formula (I) according toclaim 1 or a salt thereof with a pharmaceutically acceptable carrier. 6.A pharmaceutical composition for antagonizing an NMDA receptor whichcomprises a pharmaceutically effective amount of at least one compoundof formula (I) according to claim 1 or a salt thereof with apharmaceutically acceptable carrier.